US20020002285A1 - Process for preparing substituted pyridines - Google Patents
Process for preparing substituted pyridines Download PDFInfo
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- US20020002285A1 US20020002285A1 US09/873,740 US87374001A US2002002285A1 US 20020002285 A1 US20020002285 A1 US 20020002285A1 US 87374001 A US87374001 A US 87374001A US 2002002285 A1 US2002002285 A1 US 2002002285A1
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- acid
- process according
- alkyl
- dihydropyridine
- formula
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- 150000003222 pyridines Chemical class 0.000 title claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 5
- 239000002253 acid Substances 0.000 claims abstract description 24
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims abstract description 22
- BLLFVUPNHCTMSV-UHFFFAOYSA-N methyl nitrite Chemical compound CON=O BLLFVUPNHCTMSV-UHFFFAOYSA-N 0.000 claims abstract description 20
- 230000001590 oxidative effect Effects 0.000 claims abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- UWVBURCRJLZZKT-UHFFFAOYSA-N dimethyl 4-(4-fluorophenyl)-2,6-di(propan-2-yl)pyridine-3,5-dicarboxylate Chemical group COC(=O)C1=C(C(C)C)N=C(C(C)C)C(C(=O)OC)=C1C1=CC=C(F)C=C1 UWVBURCRJLZZKT-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- OMMWXFJGQQAQCG-UHFFFAOYSA-N dimethyl 4-(4-fluorophenyl)-2,6-di(propan-2-yl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C(C)C)NC(C(C)C)=C(C(=O)OC)C1C1=CC=C(F)C=C1 OMMWXFJGQQAQCG-UHFFFAOYSA-N 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- -1 alkali metal nitrite Chemical class 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 5
- 229910017604 nitric acid Inorganic materials 0.000 description 5
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- LFURNOQUNVHWHY-UHFFFAOYSA-N CC1=NC(C)=C(C)C(C)=C1C Chemical compound CC1=NC(C)=C(C)C(C)=C1C LFURNOQUNVHWHY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- UTNSRAORCJEGGX-UHFFFAOYSA-N II.[H]N1C(C)=C(C)C([H])(C)C(C)=C1C Chemical compound II.[H]N1C(C)=C(C)C([H])(C)C(C)=C1C UTNSRAORCJEGGX-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 238000005899 aromatization reaction Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- FVZDVXFXMXJPBA-UHFFFAOYSA-N 1-hydroxy-2H-pyridin-4-ol hydrochloride Chemical class Cl.ON1CC=C(O)C=C1 FVZDVXFXMXJPBA-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 1
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical class [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- MVFCKEFYUDZOCX-UHFFFAOYSA-N iron(2+);dinitrate Chemical class [Fe+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MVFCKEFYUDZOCX-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
Definitions
- the present invention relates to an improved process for preparing substituted pyridines by oxidation (i.e., aromatization) of the corresponding 1,4-dihydropyridines.
- Substituted pyridines are important products for the preparation of pharmaceutics, crop protection agents and dyes.
- oxidizing agents for example, supported iron nitrates and copper nitrates, if appropriate with the action of ultrasound, cerium ammonium nitrate, pyridinium chlorochromate, nitric acid, and nitrogen monoxide (see J. Org. Chem., 62, 3582 (1997) are known to be suitable for oxidizing (i.e., aromatizing) 1,4-dihydropyridines.
- oxidizing i.e., aromatizing
- 1,4-dihydropyridines Some of these oxidation methods are expensive, others require complicated apparatus and safety precautions, and others require ecologically objectionable oxidizing agents.
- the nitrogen monoxide recommended in the above literature reference for use as oxidizing agent must be handled under argon since it reacts with atmospheric oxygen and is expensive. According to J. Med.
- This invention accordingly provides a process for preparing substituted pyridines of formula (I)
- R 1 and R 5 are identical or different and each represents C 1 -C 10 -alkyl or C 6 -C 10 -aryl,
- R 3 represents hydrogen, C 1 -C 10 -alkyl or represents C 6 -C 10 -aryl that is optionally substituted by halogen, nitro, COOR 6 (wherein R 6 is C 1 -C 10 -alkyl), CN, or C 1 -C 10 -alkyl,
- R 1 to R 5 are as defined for formula (I), with methyl nitrite in the presence of an acid containing less than 20% by weight of oxidizing components.
- R 1 and R 5 are preferably identical and each preferably represents straight-chain or branched C 1 -C 6 -alkyl;
- R 2 and R 4 are preferably identical, and each preferably represents COOR 6 wherein R 6 is straight-chain or branched C 1 -C 6 -alkyl; and
- R 3 preferably represents fluorine- and/or chlorine-substituted phenyl.
- R 1 and R 5 particularly preferably represent isopropyl; R 2 and R 3 particularly preferably represent COOR 6 wherein R 6 is methyl or ethyl; and R 3 particularly preferably represents 4-fluorophenyl.
- the methyl nitrite that is required can be prepared in a simple known manner by reacting alkali metal nitrites with methanol in the presence of a strong acid.
- the methyl nitrite is obtained in gaseous form and can be used in this form for the process according to the invention. It is advantageous to use at least the amount of methyl nitrite that is stoichiometrically required. Even relatively large excesses of methyl nitrite do not interfere with the reaction. Preference is given to using from 1 to 20 mol of methyl nitrite per mole of 1,4-dihydropyridine of formula (II).
- a very wide variety of mineral and carboxylic acids are suitable for use as acids. Preference is given to using gaseous hydrogen chloride, aqueous hydrochloric acid, aqueous sulphuric acid and C 1 -C 4 -carboxylic acids in substance or as aqueous solution.
- the amount of acid can be varied within relatively wide limits. It is possible, for example, to use catalytic, stoichiometric, or superstoichiometric amounts of acid. Preference is given to using from 0.01 to 2 mols of acid per mole of 1,4-dihydropyridine of formula (II). It is also possible to use mixtures of different acids. Carboxylic acids can also act as solvent and therefore can be set in in higher molar ratios, for example up to 50 mols, preferably up to 30 mols per mol of 1,4-dihydropyridine of the formula (II).
- the acid to be used contains less than 20% by weight of oxidizing components.
- Oxidizing components can be, for example, nitric acid or salts having oxidizing action.
- the content of oxidizing components in the acid is preferably below 5% by weight.
- the acid is free of oxidizing components.
- the 1,4-dihydropyridine of formula (II) can also be employed in the form of 1,4-dihydropyridinium salts of non-oxidizing acids, for example, in the form of 1,4-dihydroxypyridine hydrochlorides. In such cases, it is possible to dispense with the separate addition of an acid.
- the acid is used in the form of an aqueous solution in such an amount that the reaction mixture forms a suspension or solution that is easy to stir, it is not necessary to add other solvents. Otherwise, it is expedient to add solvents.
- Suitable solvents are those that do not take part in any undesirable side reactions. Examples are water, aromatic hydrocarbons such as toluene, alcohols such as methanol, ethers such as dibutyl ether, halogenated hydrocarbons such as dichloroethane and chlorobenzene, sulfoxides such as dimethyl sulfoxide, and sulfones such as tetramethylene sulfone.
- Carboxylic acids can also act as solvent (see above).
- the solvents are added in such amounts that the reaction mixture forms a suspension or solution that is easy to stir.
- the 1,4-dihydropyridine of formula (II) can be suspended or dissolved in a solvent, followed by addition of the acid and introduction of gaseous methyl nitrite. It is also possible to admix the 1,4-dihydropyridine of formula (II) with such an amount of an aqueous solution of the acid that a readily stirrable suspension or solution is formed and then to introduce gaseous methyl nitrite. It is also possible to meter in the acid simultaneously but separately from the methyl nitrite.
- Suitable reaction temperatures for the process according to the invention are, for example, between ⁇ 30 and +100° C., in particular from ⁇ 10 to ⁇ 65° C.
- reaction mixture that is present after the reaction has ended can be worked up in a simple manner. If the reaction has been carried out substantially in aqueous medium, the reaction mixture can first be neutralized using any base, and the substituted pyridine of formula (I) that has been prepared can then be separated off, for example, by filtration.
- reaction has been carried out substantially in alcoholic medium or in another water-miscible solvent
- water can, after neutralization with any base, be added to the reaction mixture, and the substituted pyridine of formula (I) that has been prepared can be separated off, for example, by filtration.
- the base used for neutralizing the reaction mixture can be any base that does not take part in undesirable side reactions. Suitable bases are, for example, aqueous lyes, alkoxides as such or in alcoholic solution, and amines. If the reaction is carried out in aqueous medium, preference is given to using aqueous lyes. If the reaction is carried out in an alcoholic medium, preference is given to alkoxides.
- the process according to the invention has a number of advantages.
- the obtainable yields which are generally between 90 and 99% of theory, are high, the practice is simple, the methyl nitrite can be prepared in a simple manner as required, no ecologically objectionable heavy metal salts are used for the oxidation and, as a consequence, no highly toxic by-products are formed, and work-up of the reaction mixture is simple.
- methyl nitrite used in the examples below was prepared as required by treating a solution of I part by weight of 25% by weight strength of aqueous sodium nitrite solution and 0.14 part by weight of methanol with 0.37 part by weight of 48% by weight strength aqueous sulfuric acid and used in gaseous form for the oxidation (i.e., aromatization) according to the invention of substituted 1,4-dihydropyridines of formula (II).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to a process for preparing substituted pyridines in a simple and cost-effective manner in good yields by reacting substituted 1,4-dihydropyridines with methyl nitrite in the presence of an acid that contains less than 20% by weight of oxidizing components.
Description
- The present invention relates to an improved process for preparing substituted pyridines by oxidation (i.e., aromatization) of the corresponding 1,4-dihydropyridines.
- Substituted pyridines are important products for the preparation of pharmaceutics, crop protection agents and dyes.
- A large number of oxidizing agents, for example, supported iron nitrates and copper nitrates, if appropriate with the action of ultrasound, cerium ammonium nitrate, pyridinium chlorochromate, nitric acid, and nitrogen monoxide (see J. Org. Chem., 62, 3582 (1997) are known to be suitable for oxidizing (i.e., aromatizing) 1,4-dihydropyridines. Some of these oxidation methods are expensive, others require complicated apparatus and safety precautions, and others require ecologically objectionable oxidizing agents. The nitrogen monoxide recommended in the above literature reference for use as oxidizing agent must be handled under argon since it reacts with atmospheric oxygen and is expensive. According to J. Med. Chem., 29, 1596 (1986), the oxidation is carried out using nitric acid, but large amounts of nitric acid are required (12 ml of aqueous nitric acid for 0.66 g of starting material), and the product must be isolated by three extractions with ether.
- To prepare 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxycarbonyl)pyridine, it is known to oxidize the corresponding 1,4-dihydropyridine with sulfur (see U.S. Pat. No. 4,950,675). In addition to the problematic handling of sulfur, this process has the major disadvantage that yields of only considerably less than 40% are possible and that highly toxic hydrogen sulfide is formed as by-product.
- Thus, there is currently no process that is easy to carry out and cost-effective and gives high yields for preparing substituted pyridines by oxidation of the corresponding 1,4-dihydropyridines.
- This invention accordingly provides a process for preparing substituted pyridines of formula (I)
- wherein
- R 1 and R5 are identical or different and each represents C1-C10-alkyl or C6-C10-aryl,
- R 2 and R4 are identical or different and each represents hydrogen, C1-C10-alkyl, CN, or COOR6 wherein R6 is C1-C10-alkyl, and
- R 3 represents hydrogen, C1-C10-alkyl or represents C6-C10-aryl that is optionally substituted by halogen, nitro, COOR6 (wherein R6 is C1-C10-alkyl), CN, or C1-C10-alkyl,
- comprising reacting a substituted 1,4-dihydropyridine of formula (II)
- wherein R 1 to R5 are as defined for formula (I), with methyl nitrite in the presence of an acid containing less than 20% by weight of oxidizing components.
- In formulas (I) and (II), R 1 and R5 are preferably identical and each preferably represents straight-chain or branched C1-C6-alkyl; R2 and R4 are preferably identical, and each preferably represents COOR6 wherein R6 is straight-chain or branched C1-C6-alkyl; and R3 preferably represents fluorine- and/or chlorine-substituted phenyl.
- In formulas (I) and (II), R 1 and R5 particularly preferably represent isopropyl; R2 and R3 particularly preferably represent COOR6 wherein R6 is methyl or ethyl; and R3 particularly preferably represents 4-fluorophenyl.
- The methyl nitrite that is required can be prepared in a simple known manner by reacting alkali metal nitrites with methanol in the presence of a strong acid. In this preparation method, the methyl nitrite is obtained in gaseous form and can be used in this form for the process according to the invention. It is advantageous to use at least the amount of methyl nitrite that is stoichiometrically required. Even relatively large excesses of methyl nitrite do not interfere with the reaction. Preference is given to using from 1 to 20 mol of methyl nitrite per mole of 1,4-dihydropyridine of formula (II).
- A very wide variety of mineral and carboxylic acids are suitable for use as acids. Preference is given to using gaseous hydrogen chloride, aqueous hydrochloric acid, aqueous sulphuric acid and C 1-C4-carboxylic acids in substance or as aqueous solution.
- The amount of acid can be varied within relatively wide limits. It is possible, for example, to use catalytic, stoichiometric, or superstoichiometric amounts of acid. Preference is given to using from 0.01 to 2 mols of acid per mole of 1,4-dihydropyridine of formula (II). It is also possible to use mixtures of different acids. Carboxylic acids can also act as solvent and therefore can be set in in higher molar ratios, for example up to 50 mols, preferably up to 30 mols per mol of 1,4-dihydropyridine of the formula (II).
- The acid to be used contains less than 20% by weight of oxidizing components. Oxidizing components can be, for example, nitric acid or salts having oxidizing action. The content of oxidizing components in the acid is preferably below 5% by weight. Particularly preferably, the acid is free of oxidizing components.
- The 1,4-dihydropyridine of formula (II) can also be employed in the form of 1,4-dihydropyridinium salts of non-oxidizing acids, for example, in the form of 1,4-dihydroxypyridine hydrochlorides. In such cases, it is possible to dispense with the separate addition of an acid.
- If the acid is used in the form of an aqueous solution in such an amount that the reaction mixture forms a suspension or solution that is easy to stir, it is not necessary to add other solvents. Otherwise, it is expedient to add solvents. Suitable solvents are those that do not take part in any undesirable side reactions. Examples are water, aromatic hydrocarbons such as toluene, alcohols such as methanol, ethers such as dibutyl ether, halogenated hydrocarbons such as dichloroethane and chlorobenzene, sulfoxides such as dimethyl sulfoxide, and sulfones such as tetramethylene sulfone. Carboxylic acids can also act as solvent (see above).
- If appropriate, the solvents are added in such amounts that the reaction mixture forms a suspension or solution that is easy to stir.
- The process according to the invention can be carried out in different ways. For example, the 1,4-dihydropyridine of formula (II) can be suspended or dissolved in a solvent, followed by addition of the acid and introduction of gaseous methyl nitrite. It is also possible to admix the 1,4-dihydropyridine of formula (II) with such an amount of an aqueous solution of the acid that a readily stirrable suspension or solution is formed and then to introduce gaseous methyl nitrite. It is also possible to meter in the acid simultaneously but separately from the methyl nitrite.
- Furthermore, it is also possible, for example, to suspend 1,4-dihydropyridine of formula (II) in water and then to introduce gaseous hydrogen chloride and then methyl nitrite. Other ways of carrying out the process according to the invention are also feasible.
- Suitable reaction temperatures for the process according to the invention are, for example, between −30 and +100° C., in particular from −10 to ±65° C.
- The reaction mixture that is present after the reaction has ended can be worked up in a simple manner. If the reaction has been carried out substantially in aqueous medium, the reaction mixture can first be neutralized using any base, and the substituted pyridine of formula (I) that has been prepared can then be separated off, for example, by filtration.
- If the reaction has been carried out substantially in alcoholic medium or in another water-miscible solvent, water can, after neutralization with any base, be added to the reaction mixture, and the substituted pyridine of formula (I) that has been prepared can be separated off, for example, by filtration.
- If the reaction has been carried out in a water-immiscible medium, some or all of the solvent can, following neutralization with any base, be removed from the reaction mixture, thus giving the substituted pyridine of formula (I) that has been prepared.
- Other simple alternatives for working up the reaction mixtures are also feasible.
- The base used for neutralizing the reaction mixture can be any base that does not take part in undesirable side reactions. Suitable bases are, for example, aqueous lyes, alkoxides as such or in alcoholic solution, and amines. If the reaction is carried out in aqueous medium, preference is given to using aqueous lyes. If the reaction is carried out in an alcoholic medium, preference is given to alkoxides.
- In cases where carboxylic acids are set in the neutralization can be omitted.
- The process according to the invention has a number of advantages. Thus, the obtainable yields, which are generally between 90 and 99% of theory, are high, the practice is simple, the methyl nitrite can be prepared in a simple manner as required, no ecologically objectionable heavy metal salts are used for the oxidation and, as a consequence, no highly toxic by-products are formed, and work-up of the reaction mixture is simple.
- The methyl nitrite used in the examples below was prepared as required by treating a solution of I part by weight of 25% by weight strength of aqueous sodium nitrite solution and 0.14 part by weight of methanol with 0.37 part by weight of 48% by weight strength aqueous sulfuric acid and used in gaseous form for the oxidation (i.e., aromatization) according to the invention of substituted 1,4-dihydropyridines of formula (II).
- In a 4 liter glass reactor, 750 g of 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxycarbonyl)-1,4-dihydropyridine were initially charged in 2250 g of water and 207 g of 37% by weight strength of aqueous hydrochloric acid. 15 mol of methyl nitrite were then introduced at 60° C. After cooling to 20° C., the pH was adjusted to pH 8 using 198 g of 45% by weight strength of aqueous sodium hydroxide solution. The resulting suspension was filtered and the product that had been filtered off was washed twice with in each case 800 ml of water and then dried at 55° C. under reduced pressure. 736 g of 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxycarbonyl)pyridine were isolated, which corresponds to a yield of 98% of theory.
- In a 2 liter glass reactor, 375 g of 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxycarbonyl)-1,4-dihydropyridine were dissolved in 711.6 g of methanol at −5° C. 4 g of gaseous hydrogen chloride and 2 mol of methyl nitrite were then introduced at from −3 to −10° C. After warming to 20° C., the mixture was neutralized by adding 19.5 g of 30% by weight strength of methanolic sodium methoxide solution. The solution was heated to boiling and then admixed with 170 g of water. After cooling to +5° C., the resulting suspension was filtered and the product that had been filtered off was washed twice with in each case 400 ml of methanol/water (1:4) and then dried at 55° C. under reduced pressure. This gave 338 g of 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxycarbonyl)pyridine, which corresponds to a yield of 90.5% of theory.
- Although the invention has been described in detail in the foregoing for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be limited by the claims.
- In a 4 l glass reactor, 750 g 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxy-carbonyl)-1,4-dihydropyridine were mixed with 2250 g water and 245 g of acetic acid. Thereafter 7 mols of methyl nitrite were introduced at 58 to 60° C. After cooling to 20° C. 363 g of 45% by weight strength aqueous sodium hydroxide were added to result in an increase of the pH up to 9. The resulting suspension was filtered and the product that has been filtered off was washed twice with in each case 800 ml of water and then dried at 50 to 60° C. under reduced pressure. 708 g of 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxy-carbonyl)-pyridine were isolated, which corresponds to a yield of 95% of theory.
- In a 4 l glass reactor, 750 g 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxy-carbonyl)-1,4-dihydropyridine were mixed with 1470 g water and 1470 g of acetic acid. Thereafter 7 mols of methyl nitrite were introduced at 58 to 60° C. After cooling to 20° C. the resulting suspension was filtered and the product that has been filtered off was washed twice with in each case 800 ml of water and then dried at 50 to 60° C. under reduced pressure. 643 g of 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxy-carbonyl)-pyridine were isolated, which corresponds to a yield of 86% of theory.
Claims (10)
1. A process for preparing a substituted pyridine of formula (i)
wherein
R1 and R5 are identical or different and each represents C1-C10-alkyl or C6-C10-aryl,
R2 and R4 are identical or different and each represents hydrogen, C1C10-alkyl, CN, or COOR6 wherein R6 is C1-C10-alkyl, and
R3 represents hydrogen, C1-C10-alkyl or represents C6-C10-aryl that is optionally substituted by halogen, nitro, COOR6 (wherein R6 is C1-C10-alkyl), CN, or C1-C10-alkyl,
comprising reacting a substituted 1,4-dihydropyridine of formula (II)
wherein R1 to R5 are as defined for formula (I), with methyl nitrite in the presence of an acid containing less than 20% by weight of oxidizing components.
2. A process according to claim 1 wherein in the formulas (I) and (II) R1 and R5 are identical and represent straight-chain or branched C1-C6-alkyl; R2 and R4 are identical and represent COOR6 wherein R6 is straight-chain or branched C1-C6-alkyl; and R3 represents fluorine- and/or chlorine-substituted phenyl.
3. A process according to claim I wherein the substituted 1,4-dihydropyridine starting material is 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxycarbonyl)-1,4-dihydropyridine and the substituted pyridine product is 4-(4-fluorophenyl)-2,6-diisopropyl-3,5-di(methoxycarbonyl)-pyridine.
4. A process according to claim 1 wherein the methyl nitrite is prepared by reacting an alkali metal nitrite with methanol in the presence of a strong acid and is used in an amount of from 1 to 20 mol of methyl nitrite per mole of 1,4-dihydropyridine of formula (II).
5. A process according to claim 1 wherein the acid is a mineral or carboxylic acid used in an amount of from 0.01 to 2 mols per mole of 1,4-dihydropyridine of formula (II).
6. A process according to claim 1 wherein the 1,4-dihydropyridine of formula (II) is employed in the form of a 1,4-dihydropyridinium salt of a non-oxidizing acid and the acid is not added separately.
7. A process according to claim 1 wherein the temperature is in the range from −30 to ±100° C.
8. A process according to claim 1 wherein the acid is free of oxidizing components.
9. A process according to claims 1, wherein the gaseous hydrogen chloride, aqueous hydrochloric acid, aqueous sulfuric acid or a C1-C4-carboxylic acid in substance or as aqueous solution is used as acid.
10. A process according to claims 1, wherein a carboxylic acid is set in in an amount of up to 50 mols per mol of 1,4-dihydropyridine of formula (II).
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10028414 | 2000-06-08 | ||
| DE10028414.0 | 2000-06-08 | ||
| DE10028414 | 2000-06-08 | ||
| DE10111874A DE10111874A1 (en) | 2000-06-08 | 2001-03-13 | Improved process for the preparation of substituted pyridines |
| DE10111874.0 | 2001-03-13 | ||
| DE10111874 | 2001-03-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| US20020002285A1 true US20020002285A1 (en) | 2002-01-03 |
| US6392050B2 US6392050B2 (en) | 2002-05-21 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/873,740 Expired - Fee Related US6392050B2 (en) | 2000-06-08 | 2001-06-04 | Process for preparing substituted pyridines |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US6392050B2 (en) |
| EP (1) | EP1162197B1 (en) |
| JP (1) | JP2002020372A (en) |
| AT (1) | ATE267810T1 (en) |
| CA (1) | CA2348373A1 (en) |
| CZ (1) | CZ20012025A3 (en) |
| HU (1) | HUP0102327A3 (en) |
| IL (1) | IL143561A0 (en) |
| MX (1) | MXPA01005685A (en) |
| PL (1) | PL347965A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080300476A1 (en) * | 2007-05-31 | 2008-12-04 | Abbott Diabetes Care, Inc. | Insertion devices and methods |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4950675A (en) | 1988-12-21 | 1990-08-21 | Warner-Lambert Company | Pyridine di-mevalono-lactones as inhibitors of cholesterol biosynthesis |
| CH692199A8 (en) * | 1997-10-09 | 2002-06-14 | Cermol S.A. | PYRIDIC COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS |
-
2001
- 2001-05-28 EP EP01112068A patent/EP1162197B1/en not_active Expired - Lifetime
- 2001-05-28 AT AT01112068T patent/ATE267810T1/en not_active IP Right Cessation
- 2001-06-01 HU HU0102327A patent/HUP0102327A3/en unknown
- 2001-06-04 US US09/873,740 patent/US6392050B2/en not_active Expired - Fee Related
- 2001-06-05 JP JP2001169465A patent/JP2002020372A/en active Pending
- 2001-06-05 CA CA002348373A patent/CA2348373A1/en not_active Abandoned
- 2001-06-05 IL IL14356101A patent/IL143561A0/en unknown
- 2001-06-06 MX MXPA01005685A patent/MXPA01005685A/en not_active Application Discontinuation
- 2001-06-07 PL PL01347965A patent/PL347965A1/en not_active IP Right Cessation
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20080300476A1 (en) * | 2007-05-31 | 2008-12-04 | Abbott Diabetes Care, Inc. | Insertion devices and methods |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0102327A3 (en) | 2002-09-30 |
| EP1162197B1 (en) | 2004-05-26 |
| IL143561A0 (en) | 2002-04-21 |
| CA2348373A1 (en) | 2001-12-08 |
| MXPA01005685A (en) | 2003-08-20 |
| ATE267810T1 (en) | 2004-06-15 |
| CZ20012025A3 (en) | 2002-01-16 |
| US6392050B2 (en) | 2002-05-21 |
| HUP0102327A2 (en) | 2002-05-29 |
| EP1162197A1 (en) | 2001-12-12 |
| HU0102327D0 (en) | 2001-08-28 |
| JP2002020372A (en) | 2002-01-23 |
| PL347965A1 (en) | 2001-12-17 |
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