Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
  • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
  • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups

Definitions

• the present invention relates to a process for the preparation of 2,2-difluoroethylamine of the formula (I) and its salts, such as, for example, sulfates, hydrochlorides or acetates, starting from difluoroacetonitrile.
• 2,2-Difluoroethylamine and its salts are important intermediates for the preparation of active ingredients, in particular agrochemical active ingredients.
• Various production methods for 2,2-difluoroethylamine are known.
• Donetti et al. J. Med. Chem. 1989, 32, 957-961
• J. Med. Chem. 1989, 32, 957-961 describe, for example, the synthesis of 2,2-difluoroethylamine hydrochloride starting from 2,2-difluoroacetamide, in which the corresponding amide is treated with a diborane solution in tetrahydrofuran (THF). is reduced.
• Kluger et al. JACS 1982, 104, 10, 2891-2897 describe the reduction of 2,2-difluoroacetamide with sodium borohydride and boron trifluoride etherate to 2,2-difluoroethylamine.
• An inexpensive production process consists in the hydrogenation of difluoroacetonitrile, which is readily available as starting material. It can be prepared, for example, from difluoroacetamide (Swarts et al., Bulletin Societes Chimiques Beiges 1922, 31, 364-5), Grunewald et al., J. Med. Chem. 2006, 49 (10), 2939-2952).
• the catalytic hydrogenation of trifluoroacetonitrile using PtZ 2 is described by Gilman et al. (JACS 1943, 65 (8), 1458-1460) to give trifluoroethylamine hydrochloride.
• 2,2-difluoroethylamine of the formula (I) can be obtained by first difluoroacetonitrile of the formula (II) in a first step by catalytic hydrogenation to N (2,2-difluoroethyl) amide of the formula (III ) and then reacting the thus obtained N (2,2-difluoroethyl) amide by treatment with acid to 2,2-difluoroethylamine.
• the reaction is shown in the following reaction scheme, wherein R 1 may have the meanings given below.
• the present invention thus relates to a process for the preparation of 2,2-difluoroethylamine of the formula (I) comprising the following reaction steps
• R 1 is H, Ci_i 2 alkyl, C 3-8 cycloalkyl, Ci_i 2 haloalkyl, aryl (eg, phenyl), Ci_i 2 -alkyl-C 6 _i 0 is aryl, R 1 is preferably H, methyl , Trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, and t-butyl, n-pentyl, n-hexyl, 1, 3-dimethylbutyl, 3,3-dimethylbutyl , n-heptyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, phenyl or benzyl, more preferably H, methyl, t-butyl or phenyl. in the presence of an organic acid of general formula (IV
• R 1 has the abovementioned meaning, preferably in the presence of CF 3 COOH, CH 3 COOH, CH 3 COCl, benzoyl chloride, acetic anhydride, pivaloic anhydride, t-butyl acetic anhydride, trifluoroacetic anhydride or benzoyl anhydride or mixtures thereof, particularly preferably in the presence of CH 3 COOH, CH 3 COCl or acetic anhydride or mixtures thereof; and
• the invention further relates to the difluoroethyl amide intermediate of general formula (III) obtained by the process of the invention as defined above.
• step (a) takes place in the presence of a catalyst, wherein gaseous hydrogen is introduced into the reaction vessel or generated in situ in the reaction vessel by the use of formic acid or hydrazine and their derivatives or salts thereof.
• catalyst for the catalytic hydrogenation according to the invention in reaction step (a), it is possible to use as catalyst any catalyst known to the person skilled in the art suitable for catalytic hydrogenation.
• palladium catalysts platinum catalysts, Raney nickel catalysts, Lindlar catalysts, ruthenium and rhodium catalysts are suitable.
• Suitable catalysts preferably contain one or more metals of groups 8-10 of the Periodic Table, in particular one or more metals selected from iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium and platinum.
• the metals may be in any chemical form, eg, elemental, colloidal, as salts or oxides, together with complexing agents as chelates, or as alloys, which alloys may include other metals, such as aluminum, in addition to the metals listed above.
• the metals may be present in supported form, ie on any, preferably inorganic, support. Suitable supports are, for example, carbon (carbon or activated carbon), aluminum oxide, silicon dioxide, zirconium dioxide or titanium dioxide.
• Preferred catalysts according to the invention contain one or more metals of groups 8-10 of the periodic table on an inorganic support. Particularly preferred according to the invention are catalysts which comprise platinum and / or palladium and are optionally applied to an inorganic support. Such catalysts include PtO 2 , Pd (OH) 2 on activated carbon (Pearlman catalyst), Raney nickel, and Lindlar catalysts.
• the catalyst based on the difluoroacetonitrile used, in a concentration of about 0.01 to about 30 wt .-% is used.
• the catalyst is in a concentration of about 0.1 to about 12 wt .-% used, particularly preferably from about 0.1 to about 2 wt .-%.
• step (a) of the process according to the invention usually in a first step (i) difluoroacetonitrile and the catalyst with the organic acid, acid chloride, acid anhydride or mixtures thereof are introduced and in a second step (ii) hydrogen is introduced or generated in situ.
• steps (i) and (ii) is possible. It is also possible to hydrogenate continuously or batchwise (batchwise or batchwise).
• the catalytic hydrogenation may be carried out under overpressure (i.e., up to about 200 bar) in an autoclave or at atmospheric pressure in a hydrogen gas atmosphere. Especially at high reaction temperatures, it may be helpful to work at elevated pressure.
• the (additional) pressure increase can be effected by supplying an inert gas, such as nitrogen or argon.
• the hydrogenation according to the invention is preferably carried out at a pressure in the range of about 1 to about 100 bar, more preferably at a pressure in the range of about 5 to about 25 bar.
• reaction step (a) The organic acid, acid chloride or acid anhydride or mixtures thereof present in reaction step (a) lead to the fact that the difluoroethylamine formed is removed from the hydrogenation process and does not react with (CF 2 HCH 2 ) 2 NH.
• the necessary amount of the organic acid, acid chloride or acid anhydride present in reaction step (a), based on difluoroacetonitrile, can easily be determined by a person skilled in the art by routine experiments.
• the molar ratio of difluoroacetonitrile to the organic acid, acid chloride or acid anhydride or mixtures thereof used may be, for example, about 0.5 to 10, or about 0.9 to 2. A ratio of about 1 to 1.1 is preferred.
• the use of larger amounts of organic acid, acid chloride or acid anhydride or mixtures thereof is possible in principle, but is disadvantageous for economic reasons.
• Preferred reaction temperatures for the hydrogenation in reaction step (a) range from -20 ° C to 100 ° C, with temperatures of 0 ° C to 40 ° C being preferred.
• the reaction time of the hydrogenation is generally 30 minutes to 24 hours, with shorter or longer reaction times not adversely affecting.
• the amide of the formula (III) is reacted with a suitable acid to give 2,2-difluoroamine.
• the amide of formula (III) can also be isolated by removing the catalyst and the solvent, if present, and feeding reaction step (b).
• the acids usable in the reaction step (b) are selected from phosphoric acid (H 3 PO 4 ), sulfuric acid (H 2 S0 4 ), hydrochloric acid (HCl), hydrobromic acid (HBr), hydrofluoric acid (HF), potassium hydrogensulfate (KHSO 4 ), CF 3 COOH, CF 3 SO 3 H, CH 3 COOH, and p-tolylsulfonic acid.
• Preferred reaction temperatures for the cleavage of the difluoroamide of formula (III) in reaction step (b) range from about 0 ° C to about 100 ° C.
• solvents difluoroacetonitriles
• the catalytic hydrogenation can also be carried out without a solvent.
• Solvents are advantageously used in such an amount that the reaction mixture remains easy to stir throughout the process. It is advantageous to use, based on the difluoroacetonitrile used, 1 to 50 times the amount of solvent, preferably 2 to 40 times the amount of solvent, more preferably 2 to 30 times the amount of solvent.
• Suitable solvents for carrying out the process according to the invention are all organic solvents which are inert under the reaction conditions, the type of solvent used being of the type of reaction, in particular of the type of catalyst used and / or the source of hydrogen (introduction of gaseous hydrogen or in situ Generation). Solvents according to the invention are understood as meaning mixtures of pure solvents.
• ethers such as ethyl propyl ether, n-butyl ether, anisole, phenetole, cyclohexyl methyl ether, dimethyl ether, diethyl ether, dimethyl glycol diphenyl ether, dipropl ether, diisopropyl ether, di-n-butyl ether, diisobutyl ether, diisoamyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether , Tetrahydrofuran, methyl tetrahydrofuran, dioxane, dichloro diethyl ether and polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, heptane, octane, nonane and technical
• ethers such as eth
• Organic acids such as formic acid or acetic acid.
• water can also be used.
• the organic acid, acid chloride or anhydride present in the reaction, and mixtures thereof may also be used as the solvent.
• Preferred solvents according to the invention in the reaction step (a) are toluene, tetrahydrofuran, methyl tetrahydrofuran or mixtures thereof.
• reaction step (b) water is preferred as the solvent according to the invention.
• the work-up and purification can be carried out via the free amine or via its salts. If the 2,2-difluoroethylamine is freely present by the process according to the invention, it is, if necessary, purified by distillation. If 2,2-difluoroethylamine is in the form of a salt, the purification is carried out if necessary, preferably by crystallization.
• Preferred salts are, for example, sulfates, hydrochlorides or acetates.
• Water-soluble salts of 2,2-difluoroethylamine are generally purified by extraction from an aqueous solution.
• the free 2,2-difluoroethylamine is liberated by reacting the corresponding salt with organic or inorganic bases (eg NaHCC> 3 , Na 2 C0 3 or NaOH).
• organic or inorganic bases eg NaHCC> 3 , Na 2 C0 3 or NaOH.
• the difluoroethylamine is distilled off directly from the aqueous solution or extracted into an organic solvent.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
• Catalysts (AREA)

Priority Applications (10)

Applications Claiming Priority (4)

Publications (1)

Family

ID=41796621

Family Applications (1)

Country Status (12)

Cited By (3)

Families Citing this family (3)

Citations (1)

Family Cites Families (3)

• 2010
  • 2010-12-07 WO PCT/EP2010/069036 patent/WO2011069994A1/de not_active Ceased
  • 2010-12-07 ES ES10798990.7T patent/ES2524304T3/es active Active
  • 2010-12-07 EP EP10798990.7A patent/EP2509937B1/de not_active Not-in-force
  • 2010-12-07 IN IN5122DEN2012 patent/IN2012DN05122A/en unknown
  • 2010-12-07 JP JP2012542506A patent/JP5734997B2/ja not_active Expired - Fee Related
  • 2010-12-07 KR KR1020127017811A patent/KR101788083B1/ko not_active Expired - Fee Related
  • 2010-12-07 MX MX2012006590A patent/MX2012006590A/es active IP Right Grant
  • 2010-12-07 CN CN201080055886.XA patent/CN102741218B/zh not_active Expired - Fee Related
  • 2010-12-07 DK DK10798990.7T patent/DK2509937T3/en active
  • 2010-12-09 US US12/963,738 patent/US8242311B2/en not_active Expired - Fee Related
  • 2010-12-10 TW TW099143149A patent/TWI482749B/zh not_active IP Right Cessation
• 2012
  • 2012-05-10 IL IL219711A patent/IL219711A/en not_active IP Right Cessation

Patent Citations (1)

Non-Patent Citations (10)

Also Published As

Similar Documents

Legal Events