WO2016150937A1 - Procédé de préparation de chlorures de thiophènecarbonyle - Google Patents

Procédé de préparation de chlorures de thiophènecarbonyle Download PDF

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WO2016150937A1
WO2016150937A1 PCT/EP2016/056214 EP2016056214W WO2016150937A1 WO 2016150937 A1 WO2016150937 A1 WO 2016150937A1 EP 2016056214 W EP2016056214 W EP 2016056214W WO 2016150937 A1 WO2016150937 A1 WO 2016150937A1
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compound
formula
group
alkyl
riva
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PCT/EP2016/056214
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Florencio Zaragoza Doerwald
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Lonza Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention discloses a method for the preparation of thiophenecarbonyl chlorides starting from acetylthiophenes with thionyl chloride in the presence of a base.
  • Thiophenecarbonyl chlorides are important synthetic intermediates, for instance for the synthesis of drugs and agrochemicals. They can be prepared by a number of different routes, each having advantages and disadvantages. Of particular interest are methods that only require inexpensive starting materials and reagents, are easy to perform, and generate only small amounts of waste.
  • 2-Thiophenecarbonyl chloride is an intermediate for the preparation of Tioxazafen, a nematicide, with CAS 330459-31-9 and with the chemical name 3-phenyl-5-(thiophen-2-yl)- 1,2,4-oxadiazole and which is the compound of formula (THIOXA-1).
  • WO 2014/008257 A2 discloses the preparation of compound of formula (THIOXA-1).
  • 5 -Chloro-2 -thiophenecarbonyl chloride is an intermediate for the preparation of Rivaroxaban, an anti-thrombotic agent, with CAS 366789-02-8 and with the chemical name (S)-5-Chlor-N- ⁇ 2-0X0-3- [4-(3-oxomorpholin-4-yl)phenyl]- 1 ,3-oxazolidin-5- ylmethyl ⁇ thiophen-2-carbamid and which is compound of formula (RIVA-1).
  • US 4,321,399 discloses the preparation of 2-thiophenecarbonyl chloride by a reaction of thiophene and phosgene in the presence of aluminum chloride and in a specific and inert organic solvent.
  • thiophene is added to a premixture of phosgene and aluminum chloride in the solvent.
  • the resulting mixture must be hydrolysed immediately by pouring the resulting mixture immediately into iced aqueous hydrochloric acid.
  • the disclosure stresses the necessity of fast hydrolysis of the resulting mixture by advising a minimal continued contact of the thiophene with the premixture.
  • Adiwidjaja therefore discloses that the switch from aliphatic methyl ketones to aromatic methyl ketones lowers the yield and leads to mixtures of the desired product with by products.
  • WP 2007/008895 Al discloses in example 34 the conversion of 5-acetyl-thiophene-2- carboxylic acid with thionyl chloride to a crude acid chloride. No base is present in the reaction.
  • ambient pressure means usually 1 bar, depending on the weather
  • halogen means F, CI, Br or I, preferably CI, Br or I, more preferably CI or Br;
  • Subject of the invention is a method for the preparation of compound of formula (III);
  • the method comprises a step ST2;
  • ST2 comprises a reaction REAC2 of a compound of formula (II) with thionyl chloride
  • Rl, R2 and R3 are identical or different and independently from each other selected from the group consisting of H, halogen, C0 2 R4, C(0)C1, phenyl, 2-pyridyl, N0 2 , CN, CF 3 ,
  • R3 is selected from the group consisting of H, halogen, C0 2 R4, C(0)C1, phenyl, 2-pyridyl, N0 2 , CN, CF 3 , Ci_8 alkyl, and Ci_ 8 alkoxy;
  • R4 is Ci_6 alkyl
  • REAC2 is done in the presence of a base BAS2 or of a salt of BAS2;
  • BAS2 is selected from the group consisting of pyridine, picoline, chloropyridine, methylethylpyridine, N(R10)(R1 1)R12, l ,4-diazabicyclo[2.2.2]octane, Phe-N(R20)R21 , and mixtures thereof;
  • RIO, Rl 1 and R12 are identical or different and are independently from each other
  • R20 and R21 are identical or different and are independently from each other Ci_s alkyl; and the salt of BAS2 is selected from the group consisting of hydrochloride salt,
  • hydrobromide salt hydrogensulfate salt, sulfate salt, acetate salt and trifluoroacetate salt.
  • the C(0)C1 residue in compound of formula (III) and the C(0)CH 3 residue of compound of formula (II) are on position 2 of the thiophene ring.
  • Rl , R2 and R3 are identical or different and independently from each other selected from the group consisting of H, F, CI, Br, C0 2 R4, C(0)C1, phenyl, 2- pyridyl, N0 2 , CN, CF 3 , alkyl, and Ci_ 2 alkoxy; or
  • R3 is selected from the group consisting of H, F, CI, Br, C0 2 R4, C(0)C1, phenyl, 2- pyridyl, N0 2 , CN, CF 3 , C ⁇ alkyl, and Ci_ 2 alkoxy;
  • R4 is Ci_4 alkyl
  • Rl , R2 and R3 are identical or different and independently from each other selected from the group consisting of H, CI, Br, C02R4, N02, CN, CF3, alkyl, and Ci_ 2 alkoxy; and
  • R4 is CI -4 alkyl; more preferably, Rl , R2 and R3 are identical or different and independently from each other selected from the group consisting of H, F CI, Br, C0 2 R4, C(0)C1, phenyl, 2-pyridyl, N0 2 , CF 3 , methyl, and methoxy; or
  • R3 is selected from the group consisting of H, F CI, Br, C0 2 R4, C(0)C1, phenyl, 2-pyridyl, N0 2 , CF 3 , methyl, and methoxy;
  • R4 is Ci_2 alkyl;
  • Rl, R2 and R3 are identical or different and
  • R4 is Ci_ 2 alkyl; even more preferably, Rl is H or CI, and R2 and R3
  • compound of formula (III) is selected from the group consisting of
  • compound of formula (II) is selected from the group consisting of
  • Rl, R2 and R3 are H or Rl is CI and R2 and R3 are H.
  • compound of formula (III) is compound of formula (III- 1) or compound of formula ( ⁇ -2), and compound of formula (II) is compound of formula (II- 1) or compound of formula ( ⁇ -2) respectively.
  • the molar amount of thionyl chloride is from 2 to 50 times, more preferably from 2 to 35 times, even more preferably from 2 to 25 times, especially from 2 to 15 times, more especially from 3 to 10 times, even more especially from 3 to 7 times, based on the molar amount of compound of formula (II).
  • any excess of thionyl chloride is recycled.
  • REAC2 is done at a temperature TEMP2 of from -20 °C to 250 °C, more
  • REAC2 is done at a pressure of from ambient pressure to 100 bar, more preferably of from ambient pressure to 75 bar, even more preferably of from ambient pressure to 50 bar, especially of from ambient pressure to 30 bar, more especially of from ambient pressure to 25 bar, even more especially of from ambient pressure to 20 bar.
  • the pressure of REAC2 can be adjusted according to the chosen temperature of REAC2 and the boiling point of thionyl chloride.
  • the reaction time TIME2 of REAC2 is from 1 min to 96 h, more preferably from 5 min to 60 h, even more preferably from 5 min to 48 h, especially from 30 min to 48 h.
  • R10, Rl 1 and R12 are identical or different and are independently from each other alkyl; R20 and R21 are identical or different and are independently from each other Ci_ 2 alkyl.
  • BAS2 is selected from the group consisting of pyridine, 2-picoline, 3-picoline, 4- picoline, 2-chloropyridine, 2-methyl-5-ethylpyridine, triethylamine, tributylamine, 1,4- diazabicyclo[2.2.2]octane, ⁇ , ⁇ -dimethylaniline, and mixtures thereof;
  • BAS2 is selected from the group consisting of pyridine, 3-picoline, 2- chloropyridine, 2-methyl-5-ethylpyridine, triethylamine, tributylamine, and mixtures thereof;
  • BAS2 is selected from the group consisting of pyridine, 3-picoline, 2- chloropyridine, 2-methyl-5-ethylpyridine, and mixtures thereof.
  • BAS2 is selected from the group consisting of pyridine, picoline, chloropyridine, methylethylpyridine, and mixtures thereof;
  • BAS2 is selected from the group consisting of pyridine, 2-picoline, 3- picoline, 4-picoline, 2-chloropyridine, 2-methyl-5-ethylpyridine, and mixtures thereof; even more preferably, BAS2 is selected from the group consisting of pyridine, 3-picoline, 2- chloropyridine, 2-methyl-5-ethylpyridine, and mixtures thereof.
  • the salt of BAS2 is selected from the group consisting of hydrochloride salt, hydrobromide salt, acetate salt and trifluoroacetate salt;
  • the salt of BAS2 is selected from the group consisting of hydrochloride salt, acetate salt and trifluoroacetate salt;
  • the salt of BAS2 is selected from the group consisting of hydrochloride salt and acetate salt.
  • the molar amount of BAS2 is from 0.001 to 1 times, more preferably from 0.005 to 0.5 times, and even more preferably from 0.01 to 0.20 times, based on the molar amount of compound of formula (II).
  • REAC2 can be done in a solvent SOLV2, SOLV2 is selected from the group consisting of benzene, toluene, xylene, chlorobenzene, nitrobenzene, anisole, dichlorobenzene, dichloroethane, and mixtures thereof; preferably, SOLV2 is selected from the group consisting of toluene, o-xylene, m-xylene, p- xylene, chlorobenzene, nitrobenzene, anisole, 1,2-dichlorobenzene, 1,3-dichlorobenzene, 1 ,4-dichlorobenzene, 1 ,2-dichloroethane, and mixtures thereof;
  • SOLV2 is selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, 1 ,2-dichloroethane, and mixtures thereof.
  • the weight of SOLV2 is from 0.5 to 100 times, more preferably from 1 to 50 times, of the weight of compound of formula (II).
  • any SOLV2 is recycled.
  • ST2 can comprise after REAC2 a step ST-HEAT2, in ST-HEAT2 the reaction mixture
  • TEMP-HEAT2 is preferably from 80 °C to 250 °C, more preferably from 100 °C to 200 °C, even more preferably from 120 °C to 175 °C .
  • the time TIME-HEAT2, during which the reaction mixture is subjected to TEMP-HEAT2, is preferably from 30 min to 96 h, more preferably from 1 h to 60 h, even more preferably from 2 h to 48 h.
  • REAC2 is done at first at a temperature TEMPI for a time
  • TEMPI is from 40 to 85°C
  • TIME1 is from 2 to 60 h
  • TEMP2 is from 135 to 145°C
  • TIME2 is from 10 to 25 h; more preferably,
  • TEMP2 is from 50 to 80°C
  • TIME2 is from 3 to 10 h
  • TEMP-HEAT2 is from 135 to 145°C
  • TIME-HEAT2 is from 10 to 25 h.
  • ST-HEAT2 can be done in a solvent SOLV-HEAT2, SOLV-HEAT2 is selected from the group consisting of toluene, xylene, chlorobenzene, nitrobenzene, anisole,
  • SOLV-HEAT2 is selected from the group consisting of toluene, o-xylene, m- xylene, p-xylene, chlorobenzene, nitrobenzene, anisole, 1 ,2-dichlorobenzene, 1,3- dichlorobenzene, 1 ,4-dichlorobenzene, 1 ,2-dichloroethane, and mixtures thereof;
  • SOLV-HEAT2 is selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, 1 ,2-dichloroethane, and mixtures thereof.
  • the weight of SOLV-HEAT2 is from 0.5 to 100 times, more preferably from 1 to 50 times, of the weight of compound of formula (II).
  • any SOLV-HEAT2 is recycled.
  • ST- HEAT2 can be done under the respective necessary or higher pressure.
  • SOLV2 and SOLV-HEAT2 are used, then preferably SOLV2 and SOLV-HEAT2 are identical.
  • compound of formula (III) can be isolated and purified by methods well-known to those skilled in the art. These include, for instance, distillation, preferably fractional distillation, which can be done under reduced pressure, crystallization, extraction, or a combination of these methods.
  • compound of formula (II) is prepared in a step ST1, therefore preferably the method comprises ST1 and ST2;
  • ST1 is done before ST2;
  • ST1 comprises a reaction REAC1 of a compound of formula (I) with a compound ACET;
  • ACET is selected from the group consisting of acetyl chloride, acetic anhydride, acetic acid, ketene, and mixtures thereof;
  • Rl, R2 and R3 as defined herein, also with their embodiments.
  • ACET is selected from the group consisting of acetyl chloride, acetic anhydride, and mixtures thereof.
  • the molar amount of ACET is from 1 to 50 times, more preferably from 1 to 35 times, and even more preferably from 1 to 20 times, based on the molar amount of compound of formula (I).
  • any excess of ACET is recycled.
  • REACl is done at a temperature of from -10 °C to 200 °C, more preferably from 0
  • °C to 150 °C even more preferably from 20 °C to 125 °C.
  • REACl is done at a pressure of from ambient pressure to 25 bar, more preferably from ambient pressure to 20.
  • the pressure of REACl can be adjusted according to the chosen temperature of REACl and the boiling point of ACET.
  • reaction time of REACl is from 30 min to 24 h, more preferably from 1 h to
  • REACl is done in the presence of an acid ACIl
  • ACIl is selected from the group consisting of thionyl chloride, BF 3 -OEt 2 , perchloric acid, A1C1 3 , polymeric sulfonic acid resin, toluene sulfonic acid, HC1, H 2 S0 4 , H 3 P0 4 , Si0 2 , citric acid, tartaric acid, oxalic acid, zeolite, and mixtures thereof.
  • Zeolite can be any zeolite, preferably montmorrilonte or bentonite, more preferably
  • montmorillonite even more preferably Montmorillonite K10®, BASF, Germany (also available at Sigma Aldrich, CAS Number 1318-93-0).
  • ACIl is selected from the group consisting of thionyl chloride, BF 3 -OEt 2 ,
  • perchloric acid A1C1 3 , polymeric sulfonic acid resin, toluene sulfonic acid, HC1, H 2 S0 4 , H 3 P0 4 , Si0 2 , zeolite, and mixtures thereof;
  • ACIl is selected from the group consisting of thionyl chloride, perchloric acid, A1C1 3 , polymeric sulfonic acid resin, montmorillonite, H 3 P0 4 , and mixtures thereof; especially, ACIl is thionyl chloride, perchloric acid, A1C1 3 or H 3 P0 4 .
  • the molar amount of ACIl is from 0.001 to 1 times, more preferably from 0.005 to 0.5 times, and even more preferably from 0.01 to 0.20 times, based on the molar amount of compound of formula (I).
  • ACIl is thionyl chloride.
  • REACl can be done in a solvent SOLVl
  • SOLVl is selected from the group consisting of benzene, toluene, xylene, chlorobenzene, nitrobenzene, dichlorobenzene,
  • dichloromethane dichloroethane, carbon disulfide, and mixtures thereof;
  • SOLVl is selected from the group consisting of toluene, o-xylene, m-xylene, p- xylene, chlorobenzene, nitrobenzene, 1 ,2-dichlorobenzene, 1,3-dichlorobenzene, 1,4- dichlorobenzene, dichloromethane, 1 ,2-dichloroethane, carbon disulfide, and mixtures thereof;
  • SOLVl is selected from the group consisting of toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, dichloromethane, 1 ,2-dichloroethane, and mixtures thereof.
  • the weight of SOLVl is from 0.5 to 100 times, more preferably from 1 to 50 times, of the weight of compound of formula (I).
  • any SOLVl is recycled.
  • compound of formula (II) can be isolated and purified by methods well-known to those skilled in the art. These include, for instance, hydrolysis, distillation, preferably fractional distillation, which can be done under reduced pressure, crystallization, extraction, or a combination of these methods.
  • ACIl is thionyl chloride and is identical with the thionyl chloride of ST2.
  • ACIl is thionyl chloride and is identical with the thionyl chloride of ST2, and the solvents SOLV1 and SOLV2 are identical.
  • ACIl is thionyl
  • SOLV2 and SOLV-HEAT2 are identical.
  • STl and ST2 are done in one pot.
  • Preferred embodiments of compound of formula (I), compound of formula (II) and compound of formula (III) are those compounds wherein Rl, R2 and R3 are H or Rl is CI and R2 and R3 are H.
  • More preferred embodiments of compound of formula (I), compound of formula (II) and compound of formula (III) are compound of formula (I-l), compound of formula (1-2), compound of formula (II- 1), compound of formula ( ⁇ -2), compound of formula (III-l) and compound of formula ( ⁇ -2) respectively.
  • the method comprises the step ST2;
  • R30, R31 , R32, R33 and R34 are identical or different and independently from each other selected from the group consisting of H, halogen, CF 3 , CH 3 , OCF 3 , OCH 3 , CN and
  • step ST1 in addition to step ST2;
  • ST1 is done before ST2;
  • ST1 is as defined herein, also with all its embodiments
  • R30, R31, R32, R33 and R34 are H;
  • Rl, R2, R3, R30, R31, R32, R33 and R34 are H.
  • the method for preparation of compound of formula (THIOXA) starting from compound of formula (III) has a step ST3;
  • ST3 is done after ST2;
  • ST3 comprises a reaction REAC3, in REAC3 the compound of formula (III) is reacted with a compound of formula (IV).
  • compound of formula (III) in ST2 and in ST3 in the method for preparation of compound of formula (THIOXA) is compound of formula (III- 1) or compound of formula (III-2);
  • compound of formula (III) is compound of formula (III- 1).
  • compound of formula (IV) is selected from the group consisting of compound of formula (IV-1), compound of formula (IV-2), compound of formula (IV-3), compound of formula (IV-4), compound of formula (IV-5), compound of formula (IV-6) and compound of formula (IV-7);
  • compound of formula (IV) is compound of formula (IV- 1) or compound of formula (IV-2).
  • reaction mixture is formed.
  • REAC3 is done in the presence of a solvent SOLV3.
  • SOLV3 is a water-immiscible organic solvent.
  • SOLV3 solubilizes compound of formula (IV) and compound of formula
  • SOLV3 forms an azeotrope with water.
  • SOLV3 is selected from the group consisting of 2-methyltetrahydrofuran and butyl acetate;
  • SOLV3 is 2-methyltetrahydrofuran.
  • REAC3 is done in the presence of a base BAS3.
  • BAS3 is an aqueous base.
  • BAS3 is selected from the group consisting of sodium hydroxide, potassium
  • hydroxide lithium hydroxide, and calcium hydroxide.
  • the reaction mixture of REAC3 comprises an organic phase and an aqueous phase.
  • the pH of the aqueous phase is greater than 8, more preferably greater than 10.
  • the pH of the aqueous phase is increased or maintained by adding additional
  • the temperature of REAC3 is no greater than 85°C;
  • the temperature of REAC3 is maintained at from 55 °C to 75 °C.
  • REAC3 is done in the presence of a phase transfer catalyst PTC3.
  • PTC3 is selected from the group consisting of quaternary ammonium salts
  • PTC3 is selected from the group consisting of tetrabutylammonium
  • PTC3 is tetrabutylammonium hydroxide.
  • compound of formula (IV) is dissolved in SOLV3 prior to adding the compound of formula (III) to form the reaction mixture of REAC3.
  • REAC3 is done in the presence of water.
  • R50, R51 , R52 and R53 are identical or different and independently of one another each is selected from the group consisting of H, halogen, CF 3 , CN, N0 2 , C(0)-NH 2 ,
  • R60 and R61 are identical or different and independently of one another each is selected from the group consisting of H, Ci_ 4 alkyl and C(0)R63;
  • R63 is selected from the group consisting of Ci_ 4 alkyl-NH 2 , NH 2 , NH-Ci_ 4 alkyl,
  • R43, R44, R45, R46, R47 and R48 are identical or different and independently of one another each represents H or Ci_ 6 alkyl; wherein the method comprises the step ST2;
  • step ST1 in addition to step ST2;
  • ST1 is done before ST2;
  • ST1 is as defined herein, also with all its embodiments
  • ST4 is done after ST2;
  • ST4 comprises a reaction REAC4, in REAC4 the compound of formula (III) is reacted with a compound of formula (RIVA-Ia);
  • compound of formula (III) is compound of formula (III-2);
  • compound of formula (III) is compound of formula ( ⁇ -2) and compound of formula (RIVA-Ia) is compound of formula (RIVA-1 a).
  • compound of formula (III) in ST2 and in ST4 in the method for preparation of compound of formula (RIVA-I) is compound of formula (III-l) or compound of formula (III-2);
  • compound of formula (III) is compound of formula ( ⁇ -2).
  • REAC4 is done in a solvent SOLV4,
  • SOLV4 is selected from the group consisting of halogenated hydrocarbons, ethers, alcohols, hydrocarbons, dimethylformamide, dimethyl sulphoxide, acetonitrile, pyridine, hexamethylphosphoric triamide, water and mixtures thereof.
  • Halogenated hydrocarbons are preferably selected from the group consisting of
  • dichloromethane trichloromethane, carbon tetrachloride, 1 ,2-dichloroethane, trichloroethane, tetrachloroethane, 1 ,2-dichloroethylene and trichloroethylene.
  • Ethers are preferably selected from the group consisting of diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether and diethylene glycol dimethyl ether.
  • Alcohols are preferably selected from the group consisting of methanol, ethanol, propanol, butanol.
  • Hydrocarbons are preferably selected from the group consisting of benzene, xylene, toluene, hexane and cyclohexane.
  • REAC4 can be done in the presence of a base BAS4, BAS4 can be any customary inorganic or organic base.
  • BAS4 is preferably selected from the group consisting of alkali metal hydroxide, alkali metal carbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, potassium-tert-butoxide, amide, amine, and mixtures thereof;
  • alkali metal hydroxide is preferably sodium hydroxide or potassium hydroxide
  • alkali metal carbonate is preferably sodium carbonate or potassium carbonate
  • amide is preferably selected from the group consisting of sodium amide, lithium
  • amine is preferably selected from the group consisting of triethyl
  • BAS4 can be employed in an amount of from 1 to 5 mol, preferably from 1 to 2 mol, based on 1 mol of compound of formula (RIVA-Ia).
  • REAC4 is done at a reaction temperature of from -78 °C to reflux temperature, more preferably from 0 °C to reflux temperature, with the reflux temperature being the reflux temperature under the respective pressure.
  • REAC4 is done at a pressure of from 0.5 to 5 bar, more preferably at atmospheric pressure.
  • compound of formula (RIVA-I) is compound of formula (RIVA-1) and compound of formula (III) is compound of formula ( ⁇ -2),
  • ST5 is done after ST2;
  • ST5 comprises a reaction REAC5, in REAC5 compound of formula ( ⁇ -2) is reacted with compound of formula (RIVA-10); the reaction product of REAC5 is compound of formula (RIVA-11);
  • (RIVA-1 1) preferably, after ST5 a step ST6 is done;
  • reaction product of REAC6 is compound of formula (RIVA-13);
  • ST7 comprises a reaction REAC7, in REAC7 compound of formula (RIVA-13) is cyclized to obtain compound of formula (RIVA-1).
  • the phosgene equivalent is preferably diphosgene or triphosgene or a carbon monoxide
  • a carbon monoxide equivalent is preferably carbonyldiimidazole or disuccinimidyl carbonate.
  • Compound of formula (RIVA-10) can also be used in form of a salt thereof, preferably as a hydrochloride salt.
  • Compound of formula (RIVA-10) is a known compound and can be prepared according to known method, e.g. as disclosed in US Patent 6,107,519 or in US 2015/0133657 Al .
  • REAC5 is done in the presence of a base, such as sodium bicarbonate.
  • REAC5 is done in a solvent
  • the solvent can be ethyl acetate, hexane, water,
  • the reaction temperature of REAC5 is from 0 to 40 °C.
  • the reaction time of REAC5 is from 0.5 to 10 h.
  • the compound of formula (RIVA-11) may be isolated from the reaction mixture after REAC5 by methods including layer separation, concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
  • REAC6 is done in a solvent.
  • the solvent in REAC6 can be dichloromethane, dichloroethane, or a mixture thereof.
  • REAC6 can be done in the presence of a base,
  • the base in REAC6 can be pyridine,
  • dimethylaminopyridine triethylamine, sodium carbonate, potassium carbonate, or a mixture thereof; more preferably pyridine, triethylamine, sodium carbonate, potassium carbonate, or a mixture thereof.
  • reaction time of REAC6 is from 0.5 to 10 h.
  • the reaction temperature of REAC6 is from 0 to 35 °C.
  • the phosgen or phosgene equivalent is mixed with
  • reaction time of the first step of REAC6 is from 0.5 to 4 h.
  • the reaction temperature of the first step of REAC6 is from 5 to 25 °C.
  • reaction time of the second step of REAC6 is from 0.5 to 6 h.
  • the reaction temperature of the second step of REAC6 is from 10 to 35 °C.
  • the compound of formula (RIVA-13) may be isolated from the reaction mixture after REAC6 by methods including layer separation, concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof, and may further be dried.
  • the cyclization of REAC7 is done in a solvent.
  • the solvent in REAC7 can be
  • REAC7 can be done in the presence of a base.
  • the base in REAC7 can be potassium
  • the base in REAC7 may be added to the mixture containing the compound of formula
  • the reaction temperature of REAC7 is of from 10 to 40 °C.
  • the reaction time of REAC7 is from 2 to 15 h.
  • Compound of formula (RIVA-I), compound of formula (RIVA-II) and compound of formula (RIVA-1) may be isolated from any reaction mixture by methods including layer separation, concentration, distillation, decantation, filtration, evaporation,
  • centrifugation or a combination thereof, and may further be dried.

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  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne un procédé pour la préparation de chlorures de thiophènecarbonyle à partir d'acétylthiophènes avec du chlorure de thionyle en présence d'une base.
PCT/EP2016/056214 2015-03-25 2016-03-22 Procédé de préparation de chlorures de thiophènecarbonyle WO2016150937A1 (fr)

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EP15161389 2015-03-27
EP15163348.4 2015-04-13
EP15163348 2015-04-13
EP15171856 2015-06-12
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EP15172006.7 2015-06-15
EP15172006 2015-06-15
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EP15172236 2015-06-16
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