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
  • C07D213/80—Acids; Esters in position 3
• • 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
  • C07D213/72—Nitrogen atoms
  • C07D213/73—Unsubstituted amino or imino radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
  • C07D215/38—Nitrogen atoms

Definitions

• This invention relates generally to the amination of nitrogen-containing heterocycles by alkali metal amides, and in particular to an improved Chichibabin amination of pyridine bases.
• the base compound which undergoes amination has also received much study.
• Reports document the amination of mono and diazine ⁇ such as pyridines, quinolines, isoquinolines, benzoquinolines, phenanthridines, acridines, benzimidazoles, quinazolines, naphthyridines, pyrimidines, pyrazines and other heterocyclic systems.
• 3-substituted pyridine bases and particularly 3-alky1 derivatives, which in early work were reported to undergo Chichibabin amination to produce predominantly 2-amino-3- alkylpyridine ("2,3-isomer") and to a much lesser extent 2-amino-5-alkylpyridine (“2,5-isomer”) .
• the amination of 3-methylpyridine, also known as beta-picoline is an excellent example, which in early reports yielded the 2,3- and 2,5-isomers in a ratio of about 10.5:1.
• U.S. Patent No. 4,386,209 describes a significantly improved Chichibabin reaction which provides high 2,5- :2,3- isomer ratios.
• the improved reactions are conducted under a pressurized, ammonia-containing gas phase which is shown to favorably alter the isomer ratios obtained from the Chichibabin reaction and enable an increased production of the 2,5- isomer. Nonetheless, the reaction rates resultant of the described processes are fairly slow, and handling of the reaction mixture after hydrolysis is complicated by a substantial froth or emulsion/particulate layer.
• aminations of pyridine bases are provided in which increased reaction rates are obtained while not compromising and in some cases improving the yield of desired products and/or selectivities.
• Preferred Chichibabin aminations of the invention involve reacting a reaction mixture containing an organic solvent, a pyridine base, sodamide, and an organic additive compound which increases the rate of said reacting and is encompassed by the formula:
• X is S, 0, NR 3 , or C0 2 wherein R 1 , R 2 and R 3 are H, alkyl, aryl, or aralkyl, and n is 0 to about 12;
• Y is 0, S, or NR 6 , R 4 , R 5 and R 6 are H, alkyl, aryl, or aralkyl, and m and o are 1 to about 12;
• Z is C or S
• A is 0 or NR 9
• R 7 , R 8 and R 9 are H, alkyl, aryl or aralkyl
• B is OR 11 , NR 1 R 13 , SR 14 , C0 2 R 15 , N0 2 or CN, R 10 is alkyl, and R 11 , R 12 , R 13 , R 14 and R 15 are H, alkyl, aryl or aralkyl;
• G is -OR 16 , -ROR 17 or NR 22 R 23 wherein R 16 and R 17 are H or alkyl, and R, R 22 and R 23 are alkyl;
• the additive(s) include hydroxyalkylamino compounds of the formula (R-*- 8 ) (R 19 )N-R 20 wherein R 18 and R19, which may be the same or may differ one from the other, are -H, lower alkyl or hydroxy-substituted lower alkyl, and R20 is hydroxy-substituted lower alkyl.
• the invention thus provides an improved Chichibabin amination which comprises reacting a reaction mixture containing a pyridine base, sodamide, and an additive as identified, and an organic solvent, to aminate the pyridine base, the reacting being under a gas phase at a pressure of at least about 50 psi, the gas phase containing ammonia at a partial pressure of at least about 5 psi.
• the invention provides a process for producing an aminated pyridine base, in which a reaction mixture is formed containing a pyridine base, sodamide, and an additive as identified above, and reacting the reaction mixture to produce an aminated pyridine base.
• reaction mixture is then hydrolyzed, and the aminated pyridine base so formed is then recovered.
• the invention provides a process for increasing the rate of reaction in a Chichibabin amination.
• the process includes conducting the Chichibabin amination in a heterogeneous reaction mixture containing sodamide, a pyridine base, one or more of the above-noted additives, and an organic solvent, the reaction mixture being exposed during the amination to a nitrogen-containing gas phase at superatmospheric pressure.
• the invention also provides a preferred Chichibabin amination of a pyridine base with sodamide in the presence of an organic solvent, wherein the amination is conducted in the presence of one ore more of the above-noted additives and of a gas phase at superatmospheric pressure and containing a partial pressure of ammonia substantially equal to or greater than the autogenous pressure of ammonia generated by the reaction.
• the amination reactions of the above-described embodiments of the invention are desirably conducted in a substantially inert atmosphere at temperatures between about 100-250°C and without refluxing the mixture as is common in the classic Chichibabin reaction.
• the added ammonia may be injected in gaseous form, or left as liquid ammonia in the reaction mixture as when sodamide is prepared in situ by reacting sodium in excess liquid ammonia prior to conducting the amination.
• the temperature and pressure in the vessel are preferably maintained for a period sufficient to cause substantial amination to occur as measured by the production of hydrogen gas by the reaction, although both may vary from their initial settings.
• temperature is preferably maintained between about 130-200°C whereas reaction pressures of at least about 300 psi are preferred with at least about 15-100 psi of ammonia being initially present.
• the autogenous pressure of gases evolved during amination can be used to pressurize the reaction vessel, and excess gases can be vented off to prevent too much build up.
• Preferred processes of the invention also involve the presence of an aminopyridine in the reaction mixture, more preferably one or more of the desired products of the reaction, e.g. 2-amino-5-lower alkyl pyridine.
• a feature of the present invention is the discovery that significant and surprising results were achieved by the inclusion in a Chichibabin amination of a pyridine base of one or more organic additive compounds encompassed by the formula:
• X is S, 0, NR 3 , or C0 2 wherein R 1 , R 2 and R 3 are H, alkyl, aryl, or aralkyl, and n is 0 to about 12;
• Y is 0, S, or NR 6 , R 4 , R s and R 6 are H, alkyl, aryl , or aralkyl , and m and o are 1 to about 12 ;
• Z is C or S
• A is 0 or NR 9
• R 7 , R 8 and R 9 are H, alkyl, aryl or aralkyl
• B is OR 11 , NR 12 R 13 , SR 14 , C0 2 R 15 N0 2 or CN, R 10 is alkyl, and R 11 , R 12 , R 13 , R 14 and R 15 are H, alkyl, aryl or aralkyl;
• G is -OR 16 , -ROR 17 or NR 22 R 23 wherein R 16 and R 17 are H or alkyl and R, R 22 and R 23 are alkyl;
• alkyl refers to alkyl groups having from 1 to about 12 carbon atoms, and typically preferred alkyl groups are lower alkyl, i.e. having from 1 to about 5 carbon atoms.
• aryl refers to mono- or polycyclic aromatic compounds, preferably having up to about 30 carbon atoms. Preferred aryl groups include phenyl and napthyl groups.
• aralkyl refers to groups of the formula -alkyl-aryl, for example benzyl groups.
• additives of Formula (I) above preferred compounds occur where n is 1 to about 6, and wherein the "R" groups present (i.e. R 1 ' R 2 , etc.) are either H or lower alkyl.
• Additives of Formula II preferably also have "R" groups which are -H or lower alkyl, and further at least one of m and n is preferably at least 1. Preferred values for m and n are 0 to 6.
• Preferred Formula III additives occur where the "R" groups are lower alkyl or phenyl, and wherein Z is C and A is 0.
• Formula IV additives are preferred wherein the "R" groups are H or lower alkyl groups, and conveniently can include lower alkylamines and lower alkanols.
• pyridine compounds of Formula V are also preferred where the "R" groups are H or lower alkyl, with hydroxyl-containing pyridine compounds demonstrating advantage as shown in the Examples below.
• Formula VI and VII additives occur with preference wherein p is 2 and wherein the substituents B occur immediately next to one another on the ring (i.e. in the ortho- configuration) although meta- and para-configurations will also be suitable.
• a variety of cyclic ethers for example including relatively large ethers such as 18-crown ethers, are also suitable additives for the present invention, as are the so-called single electron transfer agents such as cumene, diphenylketone, and the like.
• Other various compounds which increase the rate of reaction are also suitable, and include for instance HMPA (hexamethylphosporamide) , tetramethylammonium acetate (TMA) , and 1-hexyne.
• a preferred group of additives from work to date includes hydroxyalkylamine compounds of the formula (R 18 ) (R-*-9)N-R 2 0 wherein R 18 and R-*- ⁇ , which may be the same or may differ one from the other, are -H, lower alkyl or hydroxy-substituted lower alkyl, and R 2 0 i s hydroxy-substituted lower alkyl.
• the additive is preferably incorporated in the reaction mixture in a molar ratio of about 0.001 to about 0.2 relative to pyridine base, and more preferably such molar ratio is about 0.02 to about 0.08.
• the applicants have discovered that the inclusion of the additive in the Chichibabin amination of 3-lower alkyl pyridines substantially improves yields of the 2,5- isomer as well as the 2,5-:2,3- isomer ratios, and in the case of hydroxyalkylamines such as monoethanolamine also improves the color of the reaction mix after hydrolysis, and alleviates frothing or emulsion problems which can be encountered in product separations following reactions not employing the hydroxyalkylamine.
• the gas phase above the mixture is initially pressurized to at least about 50 psi and ammonia added to the vessel sufficient to produce an initial partial pressure of ammonia of at least about 5 psi in this gas phase.
• the mixture is heated to a temperature sufficient to cause amination to proceed, and pressure is maintained at or above this initial 50 psi level during the course of the reaction until hydrogen evolution has substantially ceased.
• the autogenous pressure of gases evolved in situ during amination can be used to assist in maintaining pressure during the reaction, it is preferred to initially purge the vessel of air and pressurize it using an inert gas such as nitrogen, argon, etc., and then to conduct the amination in the substantially inert nitrogen atmosphere.
• an inert gas such as nitrogen, argon, etc.
• substantially is meant to define the condition that develops during amination in which evolved hydrogen and possible other gases enter the gas phase resulting in a predominant, but not totally inert nitrogen atmosphere.
• an initial ammonia pressure of at least about 15-100 psi is in the gas phase, most preferably in the range of 40-50 psi.
• sodamide is prepared in situ in the reactor by reacting sodium with excess liquid ammonia. After sodamide formation, a portion of the liquid ammonia is removed and an organic solvent added to the same vessel. The pyridine base and hydroxyalkylamine additive are then combined in the vessel.
• Enough liquid ammonia is left in the reactor so that when the mixture was brought to a temperature sufficiently high to cause amination to begin, a partial pressure of the remaining ammonia in the gas phase is provided sufficient to achieve the desired levels.
• Compounds which dissociate into free ammonia can also be provided to the reaction mixture to provide the ammonia source. More preferably, however, gaseous ammonia is directly injected into the vessel during pressurizing of the gas phase.
• the reaction mixture is maintained at a temperature sufficiently high to cause, or to permit, substantial amination to take place.
• a temperature range of between about 100-250°C is preferred, while most preferred is a range of about 130-200°C.
• Such temperature steps during the reaction have maintained advantageously high 2, 5-:2, 3- isomer ratios in the amination of 3-alkyl pyridines, while allowing the completion of the reaction more quickly.
• organic solvent lower alkyl benzenes, for example toluene and xylene, are preferred, although other organic solvents may also be used. Many such solvents are common to Chichibabin aminations.
• pyridine bases which for purposes herein include both substituted and unsubstituted pyridine bases.
• pyridine base as used herein also includes benzo derivatives of pyridine bases such as quinolines and isoquinolines.
• suitable substituted and unsubstituted pyridine bases are known, and their utilization in the present invention will be well within the purview of those skilled in the pertinent art.
• the preferred amination of the present invention is applied to a 3-lower alkyl pyridine.
• the term "lower alkyl” as used herein intends a branched or unbranched alkyl group having 1 to 5 carbon atoms.
• preferred substrates for amination will include 3- methylpyridine, 3-ethylpyridine, 3-propylpryidine, 3- isopropylpyridine, 3-butylpyridine (all butyl isomers) , and 3-pentylpyridine (all pentyl isomers) . Most preferred to date is 3-methylpyridine.
• Advantageous reactions of the invention can be conducted by adding an amount of pyridine base and the additive to a pressure vessel such as an autoclave in which sodamide has been preformed in at least a slight stoichiometric excess relative to the pyridine base.
• This addition step can be carried out at room temperature and with the prior addition of an organic solvent and optionally a dispersing agent such as oleic acid.
• the vessel is then sealed, purged of air with nitrogen, and pressurized to about 45 psi with gaseous ammonia and to about 300 psi with nitrogen in the gas phase above the solid liquid heterogeneous reaction mixture.
• the vessel and its contents were heated rapidly with stirring to between about 130-200°C at which time evolution of hydrogen gas begins, signaling the start of amination.
• the pressure in the vessel will generally increase because of this temperature rise and because of gas evolution even without further pressurizing with nitrogen gas.
• the temperature is preferably maintained in the 130-200°C range and the pressure maintained between about 300-1000 psi as a commercially practicable range, with about 350 psi being most preferred, until hydrogen evolution substantially ceases, signaling the completion of the amination.
• Excess pressure can be vented off during the reaction through a pressure relief valve or other means.
• the vessel can be allowed to cool to room temperature and vented to atmospheric pressure. The reaction mixture can then be hydrolyzed and removed, and the products of the reaction isolated using standard procedures.
• aminopyridine catalyst is also preferably included in the reaction mixture prior to pressurizing the vessel to help initiate the reaction and encourage formation of the desired product or products.
• the aminopyridine catalyst will be one or more of the desired products of the reaction, e.g. a 2-amino-3-lower alkyl pyridine or a 2-amino-5-lower alkyl pyridine, or a mixture thereof.
• the catalyst or catalyst mixture can be, for example, a portion of the reaction products of a previous amination which is not isolated but rather left in the reactor to serve a catalytic function in the subsequent amination.
• the other additives identified herein can be used in combination with one another to achieve still more beneficial properties in the amination reactions.
• mol moles
• Tol toluene
• MEA monoethanolamine
• Vol volume
• Temp temperature
• T time and is given in minutes unless otherwise noted
• Rxn reaction
• Press pressure
• mL milliliters
• L liters
• GC gas chromatography
• 2A5 2-amino-5-methylpyridine
• 2A3 2-amino-3-methylpyridine.
• the autoclave (available from Hazard Evaluation Laboratories, Limited) was equipped with automated controls for temperature, pressure, and stirring, and also with automated aquisition for temperature, pressure, stirring, and gas evolution via computer interface.
• the autoclave was first purged of air with nitrogen and pressurized to 45 psig with NH-, and further to 100 psig with N law .
• the reactor was then heated to the reaction
• the 3-methylpyridine was then added at a rate of 20 g/min until 190.2 g (2.04 mole) of feed had been added.
• the reaction was then allowed to proceed while maintaining the reactor temperature at 150°C and the pressure at 350 psig.
• the reaction is exothermic.
• the reaction was determined to be complete when the rate of gas evolution became essentially zero.
• the reactor was then cooled and vented to 150 psig.
• reaction mixture was carefully hydrolyzed with 320g water at 25-30°C and at 150 psig. The reactor was then vented to atmospheric pressure.
• the two layers were then separated.
• the aqueous layer was extracted with an additional 25-40 mL toluene and the organic layers combined.
• the organic layer was distilled in order to remove the toluene and any low boiling organic materials.
• the resulting solvent cut and concentrated a inopyridines were then sampled for GC analysis.
• the concentrate which remained after solvent removal can be further distilled to obtain the isolated 2-amino-5-lower alkyl pyridine and 2-amino-3-lower alkyl pyridine mixture and a residue.
• results from the reaction are shown in Table 1, and demonstrate that the MEA additive gave a higher 2-amino-5- methylpyridine yield and went to completion significantly faster than a similarly-conducted reaction containing no additive (Example 2).
• the MEA was found to decrease the overall reaction time by about 55% compared to the reaction containing no catalyst.
• MEA was also found to increase the 2,5-:2,3- isomer ratio from 2.90 to 4.04. The decrease in reaction time while increasing both the 2,5- isomer yield and the 2,5-:2,3- isomer ratio provide substantial advantages in the aminations and illustrates the importance of the applicants' discoveries.
• N2 was added to increase pressure to a total of 200 PSIG. With agitation the autoclave was heated to reaction temperature at which time additional nitrogen was added to give 350 psig. As the amination reaction proceeded hydrogen gas was released through the regulator and quantitated. After the reaction gas evolution subsided, the temperature was increased to 165°C, little to no additional gas evolution was observed for both runs at the elevated temperature. The reaction mixture was cooled to 25°C, gas pressure vented, and carefully hydrolyzed with
• the MEA improved the yield of 6- aminonicotinic acid and significantly improved the reaction rate.
• the MEA catalyzed run was essentially finished at 30 minutes, whereas the non-MEA catalyzed run required 95 minutes to finish.
• MEA catalyzed amination For the MEA catalyzed amination MEA (1.49 g, 5 molar % to nonylpyridine) was added to the refluxing NaNH2/toluene slurry prior to nonylpyridine addition. The reaction mixture was hydrolyzed with 45 cc of H2O added at reflux. The hydrolyzed reaction mixture was cooled and the two layers separated. The organic layer was distilled through a vigeroux column to a maximum of 295°C/1.5 mm Hg pressure. The distillate cuts and residue were analyzed by GC.
• Sodium amide was prepared in a 1.0 L 3 neck flask using 25.30 g (1.10 mole) solid Na and 1.25 g ferric nitrate catalyst in liquid NH 3 to form 1.10 mole NaNH 2 .
• the liquid ammonia was solvent exchanged with 300 mL toluene that contained 1.0 L oleic acid which was then heated to reflux for one hour.
• the NaNH 2 slurry was transferred to a autoclave as in Example 1 above with the aid of an additional 100 L toluene as wash. The autoclave was then sealed and purged with nitrogen and pressurized with nitrogen.
• the hydrolyzed reaction mixture was cooled and removed from the reactor.
• the layers were separated and the aqueous phase extracted twice with 30-40 mL aliquots of toluene.
• the layers were separated after each extraction and the organic portions combined.
• the organics were then distilled at atmospheric conditions concentrate the 2- aminopyridine and analyzed by GC.
• the standard reactions (without MEA) were similarly run at a reaction temperature of 125°C and a pressure of 150. The results showed the time of reaction was greatly reduced with the use of MEA as an additive, decreasing from approximately 500 minutes down to 220 minutes when MEA was used.

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• 1995
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