WO2013020938A1 - Method for the preparation of chlorinated pyridines - Google Patents

Method for the preparation of chlorinated pyridines Download PDF

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Publication number
WO2013020938A1
WO2013020938A1 PCT/EP2012/065312 EP2012065312W WO2013020938A1 WO 2013020938 A1 WO2013020938 A1 WO 2013020938A1 EP 2012065312 W EP2012065312 W EP 2012065312W WO 2013020938 A1 WO2013020938 A1 WO 2013020938A1
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Prior art keywords
formula
compound
group
reaction
metalcatalyst
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PCT/EP2012/065312
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French (fr)
Inventor
Florencio Zaragoza Doerwald
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Lonza Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
    • C07D213/61—Halogen atoms or nitro radicals

Definitions

  • XI is F, CI or Br; more preferably XI is Br or CI, even more preferably XI is CI, and Rl is selected from the group consisting of H, F, CI and Br, preferably of H, CI and Br.
  • compound of formula (I) is compound of formula (1-12) and compound of formula (II) is compound of formula (11-22);
  • catalyst (A) is Ru on a support (A), and support (A) is preferably charcoal.
  • reaction (A) is done or carried out in a solvent (A).
  • reaction (A) can be done in the presence of a reagent (A).
  • Reagent (A) is a reagent that reacts with water to yield hydrogen chloride or reacts with carboxylic acids to yield acyl chlorides.
  • reagent (A) is POCI 3 , oxalyl chloride or triphosgene.
  • a glass tube (approximately 4 mm inner diameter) was charged with pellets (approx 2 mm diameter) of 0.5 weight% Pd on A1 2 0 3 (0.59 g, 3 mg Pd, 28 ⁇ Pd), placed vertically in an oven, flushed with nitrogen, and the oven was heated to 370 to 380 °C. Then, under a constant stream of nitrogen, a solution of compound of formula (201) (0.48 g, 2.75 mmol) and oxalyl chloride (0.19 ml, 2.23 mmol) in chlorobenzene (9.3 ml) was pumped into the upper part of the tube within 120 min. The lower part of the tube comprising the outlet of the tube was immersed in cold (0 °C) acetonitrile (70 ml).
  • a glass tube (approximately 4 mm inner diameter) was charged with catalyst CAT (7) as defined in example 3 (2 mol-% Pd, the mol-% based on the molar amount of compound of formula (201)), placed vertically in an oven, the lower part of the tube was immersed in cold (0 °C) acetonitrile (70 ml), the tube was flushed with nitrogen, and the oven was heated to 385 °C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The invention discloses a method for the preparation of halogenated pyridines by decarbonylation of pyridine acyl halides.

Description

Method for the preparation of chlorinated pyridines
The invention discloses a method for the preparation of halogenated pyridines by
decarbonylation of pyridine acyl halides.
Chlorinated pyridines are widely used as synthetic intermediates for the preparation of insecticides, herbicides, fungicides, other crop protection agents, pharmaceuticals, and fine chemicals. US 2010/0160641 A discloses a method for producing 2,3-dihalopyridines, wherein the process comprises halogenating 3-aminopyridines with an halogenating agent in presence of ferric chloride, to obtain crude 3-amino-2-halopyridines, diazotizing the 3-amino-2- halopyridines with a nitrite salt to obtain diazonium salts, reacting the diazonium salt with halo acid in presence of a copper (I) catalyst to form crude mass of 2,3-dihalopyridines, and isolating the desired products 2,3-dihalopyridines.
This multistep synthesis proceeds under high dilution, comprises a Sandmeyer reaction and generates large amounts of inorganic and heavy metal waste; the process can not or only inadequately, dissatisfactorily and with difficulties be adapted to a continuous process technology.
Verbicky et al, Tetrahedron Letters, 1982, 23, 371-372, discloses the preparation of p- substituted chlorobenzenes by decarbonylation of p-substituted benzoyl chlorides in the gas phase at elevated temperatures with Pd on carbon as catalyst. The p-nitro substituted benzoyl chloride provides p-nitro chlorobenzene in 7% yield.
Graf R., Journal fur praktische Chemie, 1932, 134, 177-187, discloses a decarbonylation of 5,6-dichloro pyridine carbonyl chloride to 5,6-dichloro-pyridine-3-aldehyde. 2,3- dichloropyridine was observed as side product via cleavage of HCl and CO. But no chlorine was bound to the carbon previously substituted by COC1.
Pyridines are less electron rich than benzenes, and do not usually undergo reactions as those reported for benzenes. Thus, while benzenes may be chlorinated under mild conditions and with high regioselectivity, pyridines can usually only be chlorinated under harsh conditions, as reported e.g. by Pearson et al, J. Org. Chem., 1961, 26, 789-792; often yielding mixtures of isomers and poly chlorinated pyridines. Benzenes undergo Friedel-Crafts acylation under mild conditions, while pyridines can not usually be acylated with acyl halides, as reported by Jephcott et al, J. Am. Chem. Soc, 1928, 50, 1189-1192. Therefore, it is not to be generally expected that pyridines will react in the same way as benzenes.
There was a need for a method for preparation chlorinated pyridines with a method having few steps, without generating large amounts of inorganic or heavy metal waste, with good yields and the potential to implement a continuous process.
Surprisingly, it was found, that chlorinated pyridines can be prepared from pyridine carboxylic acid chlorides by catalyzed decarbonylation.
The following abbreviations are used, if not otherwise stated:
halogen means F, CI, Br or I, preferably CI, Br or I, more preferably CI or Br;
metal halide means metal fluoride, metal chloride, metal bromide or metal iodide, preferably metal chloride, metal bromide or metal iodide, more preferably metal chloride or metal bromide;
alkyl or alkane means linear, branched alkyl or alkane or cycloalkyl or cycloalkane. Subject of the invention is a method (A) for the preparation of a compound of formula (I),
Figure imgf000003_0001
method (A) comprises a reaction (A), wherein a compound of formula (II)
Figure imgf000003_0002
is contacted with a catalyst (A) at a temperature (A) of 150 to 800 °C; are identical or different and independently from each other selected from the group consisting of H, halogen, Ci_6 alkyl, CN, CF3, Ci_6 alkoxy and Ci_6 alkoxycarbonyl;
XI is F, CI or Br; catalyst (A) is selected from the group consisting of metalcatalyst (A), metalcatalyst (A) on a support (A) and mixtures thereof;
metalcatalyst (A) is a substance derived from Pd(0), Pd (I), Pd(II), Ni(0), Ni(I), Ni(II), Pt(0),
Pt(I), Pt(II), Co(0), Ru(0), lr(0), Rh(0), Rh(I), Rh(III), Ag(0), Ag(I), Cu(0), Cu(I) or
Cu(II);
support (A) is a support conventionally used for supporting metalcatalysts, which are used in organic reactions.
Reaction (A) is a decarbonylation. The contact of compound of formula (II) with catalyst (A) at a temperature (A) provides for the decarbonylation. In other words, in reaction (A) compound of formula (II) is decarbonylated at a temperature (A) in the presence of a catalyst (A).
Preferably, Rl and R2 are identical or different and independently from each other selected from the group consisting of H, halogen, Ci_4 alkyl, CN, CF3, Ci_4 alkoxy and Ci_4 alkoxycarbonyl; more preferably, Rl and R2 are identical or different and independently from each other selected from the group consisting of H, F, CI,
Br, Ci_4 alkyl, CN and CF3; even more preferably, Rl and R2 are identical or different and independently from each other selected from the group consisting of H, CI, Br, Ci_4 alkyl, CN and CF3.
Especially, R2 is H and Rl is selected from the group consisting of H, halogen, Ci_4 alkyl,
CN, CF3, Ci_4 alkoxy and Ci_4 alkoxycarbonyl; more especially Rl is selected from the group consisting of H, F, CI, Br, Ci_4 alkyl, CN and CF3; even more especially Rl is selected from the group consisting of H, CI, Br, Ci_4 alkyl, CN and CF3. In particular, R2 is H and Rl is selected from the group consisting of H, F, CI, Br, methyl, ethyl, CN, CF3; more in particular Rl is selected from the group consisting of H, F, CI, Br. Preferably, XI is Br or CI, more preferably XI is CI.
Specifically, XI is Br or CI, more preferably XI is CI, and R2 is H, and Rl is selected from the group consisting of H, F, CI and Br, preferably of H, CI and Br.
Preferably,
compound of formula (I) is compound of formula (1-1) and compound of formula (II) is
compound of formula (II- 1), or
compound of formula (I) is compound of formula (1-2) and compound of formula (II) is
compound of formula (II-2);
Figure imgf000005_0001
Figure imgf000005_0002
wherein Rl and R2 are as defined herein, also with all their preferred embodiments. More preferably,
compound of formula (I) is compound of formula (1-5) and compound of formula (II) is
compound of formula (Π-5), or
compound of formula (I) is compound of formula (1-6) and compound of formula (II) is
compound of formula (II-6);
Figure imgf000006_0001
(1-5) (II-5)
Figure imgf000006_0002
(1-6) (II-6) wherein Rl is as defined herein, also with all its preferred embodiments. Even more preferably,
compound of formula (I) is compound of formula (1-5) and compound of formula (II) is compound of formula (Π-5), or
compound of formula (I) is compound of formula (1-6) and compound of formula (II) is compound of formula (II-6);
Figure imgf000006_0003
(1-6) (II-6) XI is F, CI or Br; more preferably XI is Br or CI, even more preferably XI is CI, and Rl is selected from the group consisting of H, F, CI and Br, preferably of H, CI and Br.
Especially,
compound of formula (I) is compound of formula (I- 10) and compound of formula (II) is compound of formula (11-20), or
compound of formula (I) is compound of formula (I- 11) and compound of formula (II) is compound of formula (11-21), or
compound of formula (I) is compound of formula (1-12) and compound of formula (II) is compound of formula (11-22);
Figure imgf000007_0001
(1-10) (11-20)
Figure imgf000007_0002
(i-i i) (11-21)
Figure imgf000007_0003
(1-12) (11-22) wherein Rl is as defined herein, also with all its preferred embodiments. More especially, compound of formula (I) is compound of formula (I- 10) and compound of formula (II) is compound of formula (11-20), or
compound of formula (I) is compound of formula (1-11) and compound of formula (II) is compound of formula (11-21), or
compound of formula (I) is compound of formula (1-12) and compound of formula (II) is compound of formula (11-22);
Figure imgf000008_0001
Figure imgf000008_0002
Figure imgf000008_0003
and Rl is selected from the group consisting of H, F, CI, Br.
In particular,
compound of formula (I) is compound of formula (101) and compound of formula (II) is compound of formula (201), or
compound of formula (I) is compound of formula (102) and compound of formula (II) is compound of formula (202), or compound of formula (I) is compound of formula (103) and compound of formula (II) is compound of formula (203), or
compound of formula (I) is compound of formula (104) and compound of formula (II) is compound of formula (204).
Figure imgf000009_0001
(101) (201)
Figure imgf000009_0002
(102) (202)
Figure imgf000009_0003
(103) (203)
Figure imgf000009_0004
(104) (204)
More in particular,
compound of formula (I) is compound of formula (101) and compound of formula (II) is compound of formula (201). Preferably, metalcatalyst (A) is a substance derived from Pd(0), Pd (I), Pd(II), Ni(0), Ni(I),
Ni(II), Ru(0), Ag(0), Ag(I), Cu(0), Cu(I) or Cu(II).
More preferably, metalcatalyst (A) is a substance derived from Pd(0), Pd (I), Pd(II), Ni(0),
Ni(I), Ni(II), Ru(0), Ag(0) or Ag(I).
Even more preferably, metalcatalyst (A) is a substance derived from Pd(0), Pd (I), Pd(II) or
Preferably, support (A) is a support conventionally used for supporting metalcatalysts, which are used in heterogeneously catalyzed organic reactions.
More preferably, support (A) is carbon or an inorganic substance conventionally used for supporting metalcatalysts, which are used in heterogeneously catalyzed organic reactions.
More preferably, support (A) is selected from the group consisting of carbon, of oxides,
sulfates and carbonates of metals, said metals are selected from the group consisting of alkaline earth metals, Al, Si, Ce, Zr, La, Ti and Zn, of mixed metal oxides of said metals, of mixed metal carbonates of said metals, of mixed metal oxides carbonates of said metals and of mixtures thereof,
Preferably, mixed metallic oxides are alumosilicates, more preferably zeolithes.
Even more preferably, support (A) is selected from the group consisting of carbon, A1203, BaS04, Si02, alumosilicate and mixtures thereof.
Especially, support (A) is carbon, BaS04 or A1203.
More especially, support (A) is BaS04 or A1203.
If Pd on a support is used as catalyst (A), the support (A) is preferably A1203, BaS04 or charcoal, more preferably A1203 or BaS04.
Preferably, if metalcatalyst (A) is derived from Pd(0), Pd(I) or Pd(II), then metalcatalyst (A) is selected from the group consisting of
PdCl2, Pd(OAc)2, PdCl2(PhCN)2, PdCl2(MeCN)2, PdCl2(PPh3)2, Pd, Pd(dba)2, Pd2(dba)3, Pd(P(tBu)3)2, Pd2(P(tBu)3)3, Pd(P(l-adamantyl)3)2, Pd2(P(l- adamantyl)3)3, Pd(PPh3)4, Pd on charcoal, on A1203, or on BaS04,
and mixtures thereof;
more preferably selected from the group consisting of
Pd, PdCl2, Pd(OAc)2, Pd(dba)2, Pd2(dba)3, PdCl2(PhCN)2, PdCl2(MeCN)2, Pd on charcoal, on A1203, or on BaS04, and mixtures thereof;
even more preferably selected from the group consisting of
Pd, PdCl2, Pd(OAc)2, Pd(dba)2, Pd2(dba)3, PdCl2(MeCN)2, Pd on charcoal, on A1203, or on BaS04, and mixtures thereof;
especially selected from the group consisting of Pd, PdCl2, Pd(OAc)2, Pd2(dba)3 and Pd on charcoal, on A1203, or on BaS04;
more especially selected from the group consisting of Pd, PdCl2, Pd(OAc)2 and Pd on
charcoal, on A1203, or on BaS04. Preferably, if metalcatalyst (A) is derived from Ru(0), then catalyst (A) is Ru on a support (A), and support (A) is preferably charcoal.
Preferably, if metalcatalyst (A) is derived from Ni(0), Ni(I) or Ni(II), then catalyst (A) is Ni on a support (A), and support (A) is preferably Si02, or NiCl2
Preferably, if metalcatalyst (A) is derived from Cu(0), Cu(I) or Cu(II), then metalcatalyst (A) is selected from the group consisting of Cu, CuCl and CuCl2.
Preferably, if metalcatalyst (A) is derived from Ag(0) or Ag(I), then metalcatalyst (A) is selected from the group consisting of Ag and AgCl.
Preferably, metalcatalyst (A) is Pd, more preferably Pd(0).
Preferably, catalyst (A) is a metalcatalyst (A) on a support (A), wherein the metalcatalyst (A) is Pd(0) or Ru(0), and the support (A) is selected from the group consisting of carbon,
A1203, BaS04, Si02, alumosilicate and mixtures thereof.
More preferably, catalyst (A) is a metalcatalyst (A) on a support (A), wherein the
metalcatalyst (A) is Pd(0) or Ru(0), and the support (A) is selected from the group consisting of carbon, A1203 and BaS04. Even more preferably, catalyst (A) is a metalcatalyst (A) on a support (A), wherein the metalcatalyst (A) is Pd and the support (A) is AI2O3.
Especially, catalyst (A) is a metalcatalyst (A) on a support (A), wherein the metalcatalyst (A) is Pd(0) and the support (A) is AI2O3.
Preferably, the amount of metalcatalyst (A) is from 0.001 to 1000 mol%, more preferably from 0.001 to 100 mol%, even more preferably 0.5 to 100 mol%, the mol% being based on the molar amount of compound of formula (II). In another preferred embodiment, the amount of metalcatalyst (A) is from 0.001 to 10 mol%, more preferably from 0.05 to 5 mol%, even more preferably from 0.1 to 2 mol%, the mol% being based on the molar amount of compound of formula (II).
Preferably, when catalyst (A) comprises a support (A), the amount of support (A) is from 20% to 99.99% weight%, more preferably from 40% to 99.9% weight%, even more preferably from 70%> to 99.5%>, the % being weight%> and are based on the total weight of catalyst (A).
Preferably, reaction (A) is done at a temperature (A) of 200 to 500 °C, more preferably of 250 to 500 °C, even more preferably of 300 to 500 °C, in another even more preferred
embodiment of 250 to 400 °C.
Preferably, reaction (A) is done in gaseous phase. Preferably, reaction (A) is done at a pressure of 0.001 to 10 bar, more preferably of 0.01 to 5 bar, even more preferably of 0.5 to 2 bar.
Preferably, the reaction time of reaction (A) is from 5 min to 24 h, more preferably from 10 min to 12 h, even more preferably from 1 h to 6 h.
In one embodiment, reaction (A) is done or carried out without a solvent.
In another embodiment, reaction (A) is done or carried out in a solvent (A).
Preferably, solvent (A) is selected from the group consisting of chlorobenzene,
dichlorobenzene, toluene, xylene, trimethylbenzene, benzene, mono-, di- and tri- fluorinated benzene, chloroform, carbon tetrachloride, dichloromethane, acetonitrile, C5_i2 alkanes and mixtures thereof.
C5_i2 alkanes are preferably selected from the group consisting of pentane, hexane, heptane and methy Icy clo hexane.
More preferably, solvent (A) is selected from the group consisting of chlorobenzene, dichlorobenzene, toluene, xylene, benzene, chloroform, carbon tetrachloride,
dichloromethane, acetonitrile, pentan, hexane heptane and methy Icy clo hexane and mixtures thereof.
Even more preferably, solvent (A) is chlorobenzene, chloroform and acetonitrile.
Preferably, the amount of solvent (A) is from 0.5 to 200 fold, more preferably from 2 to 100 fold, even more preferably from 5 to 50 fold, especially from 10 to 30 fold, of the weight of compound of formula (II).
Compound of formula (II) can be added to the reactor either as a melt or as a solution in solvent (A). Optionally, reaction (A) can be done in the presence of a reagent (A). Reagent (A) is a reagent that reacts with water to yield hydrogen chloride or reacts with carboxylic acids to yield acyl chlorides.
Preferably, reagent (A) is selected from the group consisting of oxalyl chloride, POCI3, PCI5, SOCI2, phosgene, diphosgene, triphosgene, Ci_4 carboxylic acid chloride, carbon tetrachloride and mixtures thereof.
A Ci_4 carboxylic acid chloride is preferably acetyl chloride.
More preferably, reagent (A) is POCI3, oxalyl chloride or triphosgene.
Even more preferably, reagent (A) is oxalyl chloride. Preferably, the molar amount of reagent (A) is from 1 to 200 %, more preferably from 5 to 150 %, even more preferably from 10 to 100 %, the % being based on the molar amount of compound of formula (II).
Optionally, reaction (A) can be done in the presence of an oxidant (A). Preferably, oxidant (A) is selected from the group consisting of air, 02, Cl2, Br2, 12, N20, N02, sulfuryl chloride, cyanogene chloride, Ν,Ν,Ν-trichloroisocyanuric acid and mixtures thereof. More preferably, oxidant (A) is selected from the group consisting of 02, Cl2, N20, N02, cyanogene chloride and mixtures thereof.
Preferably, the molar amount of oxidant (A) is from 1 to 200 %, more preferably from 20 to 150 %, the % being based on the molar amount of compound of formula (II).
Reaction (A) can be done under inert atmosphere. Preferably, the inert atmosphere is made from a gas (A) selected from the group consisting of nitrogen, helium, neon, argon, carbon dioxide and mixtures thereof.
More preferably, gas (A) is nitrogen or carbon dioxide.
Preferably, the method (A) is done continuously, i.e. the reaction (A) is done in a continuous way, in a reactor for continuous reactions. Preferably, a melt or a mixture, preferably a solution, of compound of formula (II) in solvent (A) is continuously added into the reactor for continuous reactions, such as a tube reactor or a micro reactor, the continuous reactor is charged with catalyst (A) and heated to the desired temperature (A), and the product is removed at the other end of the reactor for continuous reactions. Preferably, the whole zone of the continuous reactor, where the catalyst (A) is located, is heated to the desired temperature (A). The time of contact of compound of formula (II) with the catalyst (A) will depend on the concentration of compound of formula (II), on the addition rate of compound of formula (A) into the continuous reactor, on the flow rate (A) of compound of formula (A) and optionally on the flow rate of an optional gas (A).
In case of a continuous method (A), the process parameters can be adjusted in such a way, that a high conversion of compound of formula (II) into compound of formula (I) is attained, but the amount of byproducts is kept low. In another embodiment, a continuous method (A) can be done in such a way, that only a low, preferably equal or below 40 %, conversion rate of compound of formula (II) into compound of formula (I) is attained, the conversion rate in % are weight % of compound of formula (I) based on the weight of compound of formula (II). Optionally in case of a continuous method (A), the crude product mixture comprising compound of formula (I) and compound of formula (II) can be fed again into the continuous reactor and subjected again to the conditions of reaction (A). Such a technique would be suitable for a continuous loop reactor set-up.
A continuous method (A) or reaction (A) has the advantage, that residence time of the product at the elevated temperature (A) and optionally in the solvent (A) can be minimized, thereby side reaction can be avoided or at least minimized. Compound of formula (I) and compound of formula (II) can be separated by conventional separation techniques, such as distillation or crystallization.
The compound of formula (I) can be isolated, purified, and analyzed using conventional techniques, well known to those skilled in the art. For instance, the gases leaving a reactor can be cooled, and the products of the reaction can be collected in a freezing trap. Alternatively, the gases leaving a reactor can be conveyed into a cold inert solvent, such as solvent (A) or dichloromethane, preferably dichloromethane, acetonitrile or toluene. The resulting solution or mixture can be distilled.
Compound of formula (I) can be purified, preferably by distillation, optionally under reduced pressure, or by crystallization.
The condensed crude products from reaction (A) can be treated with water, optionally water comprising a base, i.e. of alkaline pH, in order to hydrolyze the unreacted compound of formula (II), and compound of formula (I) can be isolated by phase separation and distillation.
Further subject of the invention is a method (A), with the method (A) as defined above, also with all its preferred embodiments,
wherein after reaction (A) a reaction (REG) is done;
wherein in reaction (REG) catalyst (A) is contacted with oxidant (REG) at a temperature
(REG) of 300 to 1000 °C;
oxidant (REG) is selected from the group consisting of air, 02, Cl2, Br2, 12, N20, N02, sulfuryl chloride, cyanogene chloride, Ν,Ν,Ν-trichloroisocyanuric acid and mixtures thereof; with catalyst (A) as defined above, also with all its preferred embodiments. Preferably, oxidant (REG) is selected from the group consisting of air, 02 and N20.
Preferably, temperature (REG) is from 400 to 900 °C. The method of the present can be performed continuously, what provides a more constant product quality than batchwise processes. A continuous process is also more convenient for the large scale production of compounds, because fewer complex operations and fewer operators are required, because no dangerous accumulation of starting materials occurs, and because the process is easier to control.
A further important andvantage of the process of the present invention is, that no inorganic or heavy metal waste but only carbon monoxide is produced as byproduct, and no large amounts of solvents and water are required. The absence of water in the process of the present invention enables the complete recycling of the unreacted compound of formula (II), and provides for dry compound of formula (I). Some of the compounds of formula (I), in particular 2- and 4-chloropyridines are water sensitive, and can react with water to form the corresponding 2- or 4-hydroxypyridines. For this reason, the absence of water in the current, new process is a further valuable feature.
Examples
List of Abbreviations and Raw materials
hexanes mixture of isomeric hexanes
THF tetrahydrofuran
quant. quantitative, i.e. 100% yield
GC Method
column: ZS-G00011 1, HP-5 ms, 30 m x 0.25 mm x 0.25 μιη
initial temperature: 60 °C
initial time: 1.0 min
number of ramps: 1
rate: 20 K/min
final temperature: 280 °C
GC-MS Method
For the GC part of GC-MS, the same above listed parameter as for GC alone were used.
GC-MS analysis of the crude product mixture of example 1 and 2 gave three main peaks. The crude product of example 1 gave the following result:
3.63 min (33% area, M+ 112, PhCl);
5.67 min (30% area, M+ 147/149, 2,3-dichloropyridine)
7.08 min (33% area, M+ 175/177, 2-chloronicotinoyl chloride)
These three peaks accounted for 96% of total peak area. None of the additional peaks accounted for more than 1.2% of the total peak area.
The identity of the peak at 5.67 min was ascertained by analyzing a commercial sample of 2,3-dichloropyridine (Aldrich) using the same GC-method as above. Retention time and mass spectrum were identical to those of crude product.
NMR Method
The molar ratio of compound of formula (II) to compound of formula (I) was determined by 1H-NMR in CDCI3 chloroform using commercially available reference substances. Example 1
A glass tube (approximately 4 mm inner diameter) was charged with pellets (approx 2 mm diameter) of 0.5 weight% Pd on A1203 (0.59 g, 3 mg Pd, 28 μιηοΐ Pd), placed vertically in an oven, flushed with nitrogen, and the oven was heated to 370 to 380 °C. Then, under a constant stream of nitrogen, a solution of compound of formula (201) (0.48 g, 2.75 mmol) and oxalyl chloride (0.19 ml, 2.23 mmol) in chlorobenzene (9.3 ml) was pumped into the upper part of the tube within 120 min. The lower part of the tube comprising the outlet of the tube was immersed in cold (0 °C) acetonitrile (70 ml).
When the addition was finished, a sample of the acetonitrile solution was concentrated to dryness, and the residue analyzed by 1H NMR, GC and GC-MS. 1H NMR indicated the product to be essentially a mixture of compound of formula (201) and compound of formula (101) in a molar ratio of 0.80 : 0.20 of compound of formula (201) : compound of formula (101). 1H NMR (400 MHz, CDC13)
2-chloronicotinic acid chloride: delta 7.46 (dd, J = 4 Hz, 6 Hz, 0.8 H), 8.41 (dd, J = 2 Hz, 6 Hz, 0.8H), 8.61 (dd, J = 2 Hz, 4 Hz, 0.8H)
2,3-dichloropyridine: delta 7.23 (dd, J = 4 Hz, 6 Hz, 0.2 H), 7.79 (dd, J = 2 Hz, 6 Hz, 0.2 H), 8.31 (dd, J = 2 Hz, 4 Hz, 0.2H)
Example 2
Example 1 was repeated with the sole difference, that the solution of compound of formula (201) and oxalyl chloride in chlorobenzene (9.3 ml) was pumped into the upper part of the tube within 30 min (and not with 120 min).
The resulting molar ratio of compound of formula (201) to compound of formula (101), as determined by 1H NMR, was 0.89 : 0.11.
NMR, GC-retention times, and MS data were equivalent to example 1. Examples 3
Example 3-1 to 3-19 were carried out with the general procedure was as follows:
A glass tube (approximately 4 mm inner diameter) was charged with catalyst CAT in an amount as given in table (1), wherein the amount is given in table (1) as mol-% of the metal of the catalyst, the mol-% being based on the molar amount of compound of formula (201); in case that CAT was in form of pellets, the diameter of the pellets was approx 2 mm; placed vertically in an oven, the lower part of the tube comprising the outlet was immersed in cold (0 °C) acetonitrile (70 ml), the tube was flushed with nitrogen, and the oven was heated to the first temperature TEMP given in table (1). Then, under a constant stream of nitrogen as a carrier gas, wherein only in example 3-12 the carrier gas C02 instead of nitrogen was used, a solution of compound of formula (201) (0.5 g; except for example 3-19, where 200 mg were used instead of 0.5 g) and oxalyl chloride (0.83 mol equivalents, the mol equivalents based on the molar amount of compound of formula (201); except for examples 3-5, 3-15 and 3-19, where no oxalyl chloride was used, and except for example 3-6, where 0.28 mol equivalents of triphosgene was used, the mol equivalents based on the molar amount of compound of formula (201)) in the solvent chlorobenzene, wherein only in example 3-5 the solvent chloroform instead of chlorobenzene was used, was pumped into the upper part of the tube within dosing time DOS. The temperature during dosing was in the range of the first temperature TEMP to the second temperature TEMP as given in table (1).
The concentration of compound of formula (201) with respect to solvent was 5 % by weight of compound of formula (201), the % by weight based on the weight of the combined amount of compound of formula (201) and solvent; except for example 3-5, where 10 % by weight were used, and except for example 3-19, where 16 % by weight were used, instead of said 5 % by weight.
The effluent condensed in said acetonitrile.
Further details of examples 3-1 to 3-19 are given in table (1).
Table (1)
Ex Catalyst DOS TEMP Ratio yield
CAT Amount (10) (11)
[mol-%] [min] [°C] [%]
3-1 (5) 1 120 375, 380 1:0.24 nd
3-2 (5) 1 30 375, 385 1:0.13 nd
3-3 (8) 2 60 380, 395 1:0.83 43
3-4 (9) 2 60 380, 390 1:0.21, 1:0.13 7
3-5 (14) 2 60 390, 405 1:0.04 3.5
3-6 (8) 2 60 380, 400 1:0.8, 1:3.57, 1:2.38 20
3-7 (8) 2 60 450, 475 1:25, 1:3.6, 1:1.3 41
3-8 (8) 2 60 300, 315 1:0.58, 1:0.451:0.26 16
3-9 (8) 2 60 380, 396 1:52, 1:8, 1:2.4 42
3-10 (5) 1 60 377, 390 1:0.06, 1:0.11, 1:0,11 8
3-11 (5) 1 60 375, 395 1:0.12, 1:0.12, 1:0.14 6
3-12 (8) 2 60 376, 390 1:2.8, 1:1.5, 1:0.91 36
3-13 (13) 2 60 374, 390 1:0.006, 1:0.001, 1:0.01 0.4
3-14 (?) 0.5 60 370, 390 1:0.46, 1:0.20, 1:0.46 24
3-15 (8) 1 60 340, 380 1:0.45, 1:0.12 9
3-16 (V) 5 60 374, 380 1:38, 1:23 nd
3-17 (5) 5 60 374, 387 1:0.25, 1:0.33, 1:0.59 nd
3-18 (?) 2 60 379, 387 1:0.55, 1:0.36, 1:0.30, nd
1:0.14, 1:0.13
3-19 (8) 3 25 395, 400 1:0.79 nd not determined
0.5 % by weight, the % by weight being based on the total weight of the catalyst, of Pd on A1203, as pellets
0.5 % by weight, the % by weight being based on the total weight of the catalyst, of Pd on AI2O3, as powder
10 % by weight, the % by weight being based on the total weight of the catalyst, of Pd on C, as powder (9) 5 % by weight, the % by weight being based on the total weight of the catalyst, of Ru on C, as powder
(10) A sample of the condensate was concentrated to dryness, and the residue analyzed by 1H NMR. Table (1) gives the molar ratio of compound of formula (201) : compound of formula (101).
If one ratio is given, the sample was taken when the dosing was finished.
If two ratios are given, the first sample giving the first ratio was taken when the dosing was half finished, the second sample giving the second ratio was taken when the dosing was finished.
If three ratios are given, the first sample giving the first ratio was taken when the
dosing was one third half finished, the second sample giving the second ratio was taken when the dosing was two third finished, and the third sample giving the third ratio was taken when the dosing was finished.
If five ratios are given, a total of five samples were taken after one fifth, after two fifth, after three fifth, after four fifth and at the end of the dosing time.
(11) a sample of the final condensate, after dosing was finished, was used to determine the yield of compound of formula (101) by 1H NMR with an internal standard, the yield is given in mol-%, the mol-% being based on the molar amount of compound of formula (201)
(13) 10 % by weight, the % by weight being based on the total weight of the catalyst, of Pd on BaS04, as powder
(14) PdCl2 as powder
In example 3-19 compound of formula (202) was used instead of compound of formula (201), and compound of formula (102) was the product instead of compound of formula (101), the therefore any molar amounts are based on compound of formula (202) and not on compound of formula (201).
Examples 4
For a first dosing, a glass tube (approximately 4 mm inner diameter) was charged with catalyst CAT (7) as defined in example 3 (2 mol-% Pd, the mol-% based on the molar amount of compound of formula (201)), placed vertically in an oven, the lower part of the tube was immersed in cold (0 °C) acetonitrile (70 ml), the tube was flushed with nitrogen, and the oven was heated to 385 °C. Then, under a constant stream of nitrogen as a carrier gas, a solution of compound of formula (201) (0.5 g, 2.8 mmol) and oxalyl chloride (0.83 mol equivalents, the mol equivalents based on the molar amount of compound of formula (201)) in the solvent chlorobenzene was pumped into the upper part of the tube within 60 min. The temperature during dosing was from 385 to 394 °C.
The concentration of compound of formula (201) with respect to the solvent was 5 % by weight of compound of formula (201), the % by weight based on the weight of the combined amount of compound of formula (201) and solvent.
The effluent condensed in said acetonitrile.
After this first dosing the catalyst was heated to 450 °C and was contacted with air at 450°C. Then a second dosing was done in analogy to the first dosing with the sole difference, that the temperature range during the second dosing was from 380 to 396 °C.
The ratios in analogy to example 3 (10) were for the first dosing 1 : 3.8, 1 : 1.55, 1 :0.60, and for the second dosing 1 :3.8, 1 :0.60, 1 :0.30.

Claims

Claims
1. A method (A) for the preparation of a compound of formula (I),
Figure imgf000023_0001
method (A) comprises a reaction (A), wherein a compound of formula (II)
Figure imgf000023_0002
is contacted with a catalyst (A) at a temperature (A) of 150 to 800 °C; are identical or different and independently from each other selected from the group consisting of H, halogen, Ci_6 alkyl, CN, CF3, Ci_6 alkoxy and Ci_6 alkoxycarbonyl;
XI is F, CI or Br; catalyst (A) is selected from the group consisting of metalcatalyst (A), metalcatalyst (A) on a support (A) and mixtures thereof;
metalcatalyst (A) is a substance derived from Pd(0), Pd (I), Pd(II), Ni(0), Ni(I), Ni(II), Pt(0),
Pt(I), Pt(II), Co(0), Ru(0), lr(0), Rh(0), Rh(I), Rh(III), Ag(0), Ag(I), Cu(0), Cu(I) or
Cu(II);
support (A) is a support conventionally used for supporting metalcatalysts, which are used in organic reactions.
2. Method (A) according to claim 1 , wherein Rl and R2 are identical or different and independently from each other selected from the group consisting of H, halogen, Ci_4 alkyl, CN, CF3, Ci_4 alkoxy and Ci_4 alkoxycarbonyl.
3. Method (A) according to claim 1 or 2, wherein
XI is CI or Br.
4. Method (A) according to one or more of claims 1 or 3, wherein
compound of formula (I) is compound of formula (1-1) and compound of formula (II) is compound of formula (II- 1), or
compound of formula (I) is compound of formula (1-2) and compound of formula (II) is compound of formula (Π-2).
Figure imgf000024_0001
Figure imgf000024_0002
5. Method (A) according to one or more of claims 1 or 3, wherein
compound of formula (I) is compound of formula (1-5) and compound of formula (II) is compound of formula (Π-5), or
compound of formula (I) is compound of formula (1-6) and compound of formula (II) is compound of formula (Π-6).
Figure imgf000025_0001
(1-5) (II-5)
Figure imgf000025_0002
(1-6) (II-6)
6. Method (A) according to one or more of claims 1 to 5, wherein
metalcatalyst (A) is a substance derived from Pd(0), Pd (I), Pd(II), Ni(0), Ni(I), Ni(II), Ru(0), Ag(0), Ag(I), Cu(0), Cu(I), Cu(II).
7. Method (A) according to one or more of claims 1 to 6, wherein
catalyst (A) is a metalcatalyst (A) on a support (A), wherein the metalcatalyst (A) is Pd(0) or Ru(0), and the support (A) is selected from the group consisting of carbon, A1203, BaS04, Si02, alumosilicate and mixtures thereof.
8. Method (A) according to one or more of claims 1 to 7, wherein
reaction (A) is done at a temperature (A) of 200 to 500 °C.
9. Method (A) according to one or more of claims 1 to 8, wherein
reaction (A) is done in gaseous phase.
10. Method (A) according to one or more of claims 1 to 9, wherein
reaction (A) is done in a solvent (A); solvent (A) is selected from the group consisting of chlorobenzene, dichlorobenzene, toluene, xylene, trimethylbenzene, benzene, mono-, di- and tri- fluorinated benzene, chloroform, carbon tetrachloride, dichloromethane, acetonitrile, C5_i2 alkanes and mixtures thereof.
1 1. Method (A) according to claim 10, wherein
solvent (A) is chlorobenzene, chloroform and acetonitrile.
12. Method (A) according to one or more of claims 1 to 1 1 , wherein
reaction (A) is done in the presence of a reagent (A), reagent (A) is selected from the group consisting of oxalyl chloride, POCI3, PCI5, SOCl2, phosgene, diphosgene, triphosgene, Ci_4 carboxylic acid chloride, carbon tetrachloride and mixtures thereof.
13. Method (A) according to claim 12, wherein
reagent (A) is POCI3, oxalyl chloride or triphosgene.
14. Method (A) according to one or more of claims 1 to 13, wherein
method (A) is done continuously.
15. Method (A) according to one or more of claims 1 to 14, wherein
wherein after reaction (A) a reaction (REG) is done;
wherein in reaction (REG) catalyst (A) is contacted with oxidant (REG) at a temperature
(REG) of 300 to 1000 °C; wherein
oxidant (REG) is selected from the group consisting of air, 02, Cl2, Br2, 12, N20, N02, sulfuryl chloride, cyanogene chloride, Ν,Ν,Ν-trichloroisocyanuric acid and mixtures thereof.
PCT/EP2012/065312 2011-08-08 2012-08-06 Method for the preparation of chlorinated pyridines WO2013020938A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0239905A1 (en) * 1986-03-31 1987-10-07 Makhteshim Chemical Works Limited Vapor phase production of Chlorinated pyridines from alpha-picoline
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EP0239905A1 (en) * 1986-03-31 1987-10-07 Makhteshim Chemical Works Limited Vapor phase production of Chlorinated pyridines from alpha-picoline
US5247093A (en) * 1992-12-15 1993-09-21 Reilly Industries, Inc. Chlorination process
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