US2702802A - Process of making isocinchomeronic acid and decarboxylation of same to niacin - Google Patents

Process of making isocinchomeronic acid and decarboxylation of same to niacin Download PDF

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US2702802A
US2702802A US263709A US26370951A US2702802A US 2702802 A US2702802 A US 2702802A US 263709 A US263709 A US 263709A US 26370951 A US26370951 A US 26370951A US 2702802 A US2702802 A US 2702802A
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niacin
acid
decarboxylation
isocinchomeronic
making
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Robert S Aries
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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
    • C07D213/78—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

Definitions

  • This invention relates to an improved process for making niacin from 2,5-dialkyl pyridines, and more particularly from the readily available Z-methyl-S-ethyl-pyridine by oxidation with nitric acid to isocinchomeronic acid followed by decarboxylation to niacin.
  • Niacin more commonly termed nicotinic acid, is one of the B-complex vitamins essential for growth and the prevention and cure of pellagra, and as such it is in demand as an additive to thehurnan dietv and as av general animal feed supplement.
  • the principal object of the present invention is to improve existing methods for making niacin involving the oxidation of the 2,5-dialkyl pyridines by nitric acid.
  • niacin has been to cause a 2,5-dialkyl pyridine, and particularly 2- rnethyl-S-ethyl-pyridine, to react with nitric acid under conditions of superatmospheric pressures and elevated temperatures, e. g., 185 C. and above, to yield niacin in a single operation, even though essentially two reactions are involved, namely, oxidation of the 2,5-dialkyl pyridine to isocinchomeronic acid, followed by decarboxylation of the latter to niacin.
  • Optimum conditions for the decarboxylation reaction involve a temperature range of l85l90 C. or higher.
  • the oxidation reaction proceeds at a lowertemperature, e. g., from 155 to 188 C., with satisfactory results to be had at the lower temperature range.
  • a lowertemperature e. g., from 155 to 188 C.
  • the oxidation reaction is carried out at the higher temperatures best suited for the decarboxylation reaction, it is found that the nitric acid mixture present is extremely corrosive to stainless steel, the only structural material readily available for a reaction chamber within which to carry out the reaction.
  • costly tantalum or platinum lined equipment has been recommended for the combined oxidation-decarboxylation reactions.
  • Stainless Steel Type Liquid Vapor Local corrosion rates may far exceed the overall corrosion rates shown above. This may be attributed to unavoidable difierences in metallurgy at various points in the stainless steel. These differences are to be ascribed to variations in the manufacture of the steel, the fabrication of the vessel, and the heat treatment process. In addition, I have found that the decarboxylation reaction, especially at the lower temperatures, is slower than the oxidation reaction and is responsible for a long holdup in the time required to efiect substantially complete conversion of the isocinchomeronic acid to niacin. Because of this, large equipment is required, thereby increasing the total corrosion involved.
  • a further object is to provide an improved process of converting isocinchomeronic acid to niacin.
  • a still further object is to devise an improved process of recovering the produced niacin in the form of a niacin ester.
  • I therefore preferably react Z-methyl-5-ethyl-pyridine with nitric acid at temperatures from to C. to form principally isocinchomeronic acid.
  • I then separate the isocinchomeronic acid from the reaction products and convert it to niacin, preferably in absence of nitric acid and employing temperatures best suited for this reaction in the range of 180-190 C. or higher, whereby the reaction is carried out under conditions which are not corrosive and which in some instances, if desired, do not require the use of pressure equipment.
  • the decarboxylation to niacin may be carried out in small compact, relatively inexpensive equipment.
  • the isocinchomeronic acid may be separated from the reaction mixture by adjusting its pH to 1.0-2.0, preferably 1.5. Normally, by proper choice of feed rate, feed composition, temperature and pressure, this range of pH may be automatically had. Then the reaction mixture is cooled to 25 C. and the precipitate filtered off and washed or reslurried with a small amount of water to remove traces of nitric acid, thereby yielding a product which is essentially isocinchomeronic acid. It is then slurried in a solvent medium or vehicle hereinafter disclosed, and therein subjected to temperatures from 180 to C. or higher.
  • the medium can be so chosen that no pressure is required to reach the desired temperature or, in any event, one that is no higher than that of the vapor pressure of the medium at the temperature used.
  • non-reactive media which I prefer may be mentioned the following: water, commercial heat transfer oil (consisting of high boiling hydrocarbons) sulfuric acid and various organic solvents such as cyclohexanone.
  • I may advantageously recover the produced niacin in the form of an ester by adding to the acid mixture a slight excess of a lower, saturated, aliphatic alcohol, then heating the mixture with agitation and under reflux until esterification is complete, then cooling, neutralizing and extracting with a suitable solvent. After removal of the extract by distillation, the niacin ester may then be refined by subjecting it to distillation and recovering the pure niacin ester as the distillate.
  • Example 1 cient Wash water was used to make all transfers of precipitates quantitative.
  • the wet precipitate was charged into the rocker bomb with 50 cc. of distilled water.
  • the mixture was heated as described in Example 2.
  • the reaction product was found to contain 3.0 grams of niacin and no isocinchomeronic acid.
  • Example 2 10 grams of isocinchomeronic acid and 100 grams of water were charged to 250 cc. rocker bomb. The mixture was heated to 205 C. and maintained at this temperature for 2 hours. An analysis of the reaction product showed that 94 mole percent of the isocinchomeronic acid was'converted to niacin and only a slight trace of ISO- cinchomeronic acid could be detected.
  • Example 3 10 grams of isocinchomeronic acid were heated in a glass beaker with 50 ml. of concentrated sulfuric acid with agitation until the evolution of carbon dioxide was complete. On cooling and neutralizing, analysis showed that 96 mole percent of the dicarboxylic acid had been converted to niacin.
  • Example 5 Example 4 was repeated except that to the cooled reaction product was added 50 grams of denatured alcohol and the mixture was refluxed for eight hours. The reaction product was neutralized with ammonium hydroxide over cracked ice. The cold alkaline solution was extracted three times with ether. The combined ether extracts were dried over anhydrous sodium sulfate and distilled under vacuum after the ether was removed. Ethyl nicotinate was obtained as the reaction product.
  • niacin from isocinchomoronic acid by the decarboxylation thereof by heat with recovery of the niacin produced, characterized by mixing isocinchomeronic acid in a non-reactive, substantially non-corrosive liquid vehicle selected from the group consisting of water, high temperature heat transfer oil, concentrated sulfuric acid and cyclohexanone, and heating the mixture to a decarboxylating temperature range above 180 C. and maintaining such temperature range until the decarboxylation is substantially complete.
  • a non-reactive, substantially non-corrosive liquid vehicle selected from the group consisting of water, high temperature heat transfer oil, concentrated sulfuric acid and cyclohexanone
  • niacin from isocinchomeronic acid by the decarboxylation thereof by heat with recovery of the niacin produced characterized by mixing isocinchomeronic acid in cyclohexanone, and heating the mixture to a decarboxylating temperature range above 180 C. and maintaining such temperature range until the decarboxylation is substantially complete.

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  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)

Description

United States Patent PROCESS OF MAKING ISOCINCHOMERONIC ACID AND DECARBOXYLATION OF SAL IE TO NIACIN Robert S. Aries, New York, N. Y.
No Drawing. Application December 27, 1951, Serial No. 263,709
5 Claims. (Cl. 260-2955) This invention relates to an improved process for making niacin from 2,5-dialkyl pyridines, and more particularly from the readily available Z-methyl-S-ethyl-pyridine by oxidation with nitric acid to isocinchomeronic acid followed by decarboxylation to niacin.
Niacin, more commonly termed nicotinic acid, is one of the B-complex vitamins essential for growth and the prevention and cure of pellagra, and as such it is in demand as an additive to thehurnan dietv and as av general animal feed supplement.
The principal object of the present invention is to improve existing methods for making niacin involving the oxidation of the 2,5-dialkyl pyridines by nitric acid.
Heretofore a common method of making niacin has been to cause a 2,5-dialkyl pyridine, and particularly 2- rnethyl-S-ethyl-pyridine, to react with nitric acid under conditions of superatmospheric pressures and elevated temperatures, e. g., 185 C. and above, to yield niacin in a single operation, even though essentially two reactions are involved, namely, oxidation of the 2,5-dialkyl pyridine to isocinchomeronic acid, followed by decarboxylation of the latter to niacin. Optimum conditions for the decarboxylation reaction involve a temperature range of l85l90 C. or higher. The oxidation reaction, on the other hand, proceeds at a lowertemperature, e. g., from 155 to 188 C., with satisfactory results to be had at the lower temperature range. However, when the oxidation reaction is carried out at the higher temperatures best suited for the decarboxylation reaction, it is found that the nitric acid mixture present is extremely corrosive to stainless steel, the only structural material readily available for a reaction chamber within which to carry out the reaction. Thus, in the prior art costly tantalum or platinum lined equipment has been recommended for the combined oxidation-decarboxylation reactions.
Investigation of the effect of corrosion of the abovementioned oxidation reaction products at temperatures 185-190 C. on stainless steel has yielded the following data:
Stainless Steel Type Liquid Vapor Local corrosion rates may far exceed the overall corrosion rates shown above. This may be attributed to unavoidable difierences in metallurgy at various points in the stainless steel. These differences are to be ascribed to variations in the manufacture of the steel, the fabrication of the vessel, and the heat treatment process. In addition, I have found that the decarboxylation reaction, especially at the lower temperatures, is slower than the oxidation reaction and is responsible for a long holdup in the time required to efiect substantially complete conversion of the isocinchomeronic acid to niacin. Because of this, large equipment is required, thereby increasing the total corrosion involved.
It is therefore a more specific object of my invention to provide an improved process in which the oxidation reaction to isocinchomeronic acid is carried out separately from the decarboxylation reaction to niacin under conditions best suited for each, with the consequent saving of equipment life and with other substantial advantages to be mentioned.
ICC
A further object is to provide an improved process of converting isocinchomeronic acid to niacin.
A still further object is to devise an improved process of recovering the produced niacin in the form of a niacin ester.
In carrying out my invention I therefore preferably react Z-methyl-5-ethyl-pyridine with nitric acid at temperatures from to C. to form principally isocinchomeronic acid. I then separate the isocinchomeronic acid from the reaction products and convert it to niacin, preferably in absence of nitric acid and employing temperatures best suited for this reaction in the range of 180-190 C. or higher, whereby the reaction is carried out under conditions which are not corrosive and which in some instances, if desired, do not require the use of pressure equipment. Furthermore, by using a concentrated solution or slurry of isocinchomeronic acid as compared to that normally present in the reactor, the decarboxylation to niacin may be carried out in small compact, relatively inexpensive equipment.
I have found that the isocinchomeronic acid may be separated from the reaction mixture by adjusting its pH to 1.0-2.0, preferably 1.5. Normally, by proper choice of feed rate, feed composition, temperature and pressure, this range of pH may be automatically had. Then the reaction mixture is cooled to 25 C. and the precipitate filtered off and washed or reslurried with a small amount of water to remove traces of nitric acid, thereby yielding a product which is essentially isocinchomeronic acid. It is then slurried in a solvent medium or vehicle hereinafter disclosed, and therein subjected to temperatures from 180 to C. or higher. If desired, the medium can be so chosen that no pressure is required to reach the desired temperature or, in any event, one that is no higher than that of the vapor pressure of the medium at the temperature used. Among the non-reactive media which I prefer may be mentioned the following: water, commercial heat transfer oil (consisting of high boiling hydrocarbons) sulfuric acid and various organic solvents such as cyclohexanone.
Especially when sulfuric acid has been used as the vehicle, I may advantageously recover the produced niacin in the form of an ester by adding to the acid mixture a slight excess of a lower, saturated, aliphatic alcohol, then heating the mixture with agitation and under reflux until esterification is complete, then cooling, neutralizing and extracting with a suitable solvent. After removal of the extract by distillation, the niacin ester may then be refined by subjecting it to distillation and recovering the pure niacin ester as the distillate.
My invention will be best understood by reference to the following illustrative examples:
Example 1 cient Wash water was used to make all transfers of precipitates quantitative. The wet precipitate was charged into the rocker bomb with 50 cc. of distilled water. The mixture was heated as described in Example 2. On completion of the reaction, the reaction product was found to contain 3.0 grams of niacin and no isocinchomeronic acid.
T he reaction between Z-methyl-S-ethyl-pyridine and nitric acid was repeated using the quantities and conditions as described above. The reaction mixture was found to contain 27 mole percent isocinchomeronic acid based on the 2-methyl-5-ethyl-pyridine charged.
Example 2 10 grams of isocinchomeronic acid and 100 grams of water were charged to 250 cc. rocker bomb. The mixture was heated to 205 C. and maintained at this temperature for 2 hours. An analysis of the reaction product showed that 94 mole percent of the isocinchomeronic acid was'converted to niacin and only a slight trace of ISO- cinchomeronic acid could be detected.
Example 3 10 grams of isocinchomeronic acid were heated in a glass beaker with 50 ml. of concentrated sulfuric acid with agitation until the evolution of carbon dioxide was complete. On cooling and neutralizing, analysis showed that 96 mole percent of the dicarboxylic acid had been converted to niacin.
Example 5 Example 4 was repeated except that to the cooled reaction product was added 50 grams of denatured alcohol and the mixture was refluxed for eight hours. The reaction product was neutralized with ammonium hydroxide over cracked ice. The cold alkaline solution was extracted three times with ether. The combined ether extracts were dried over anhydrous sodium sulfate and distilled under vacuum after the ether was removed. Ethyl nicotinate was obtained as the reaction product.
I claim:
' 1. The method of making niacin from isocinchomoronic acid by the decarboxylation thereof by heat with recovery of the niacin produced, characterized by mixing isocinchomeronic acid in a non-reactive, substantially non-corrosive liquid vehicle selected from the group consisting of water, high temperature heat transfer oil, concentrated sulfuric acid and cyclohexanone, and heating the mixture to a decarboxylating temperature range above 180 C. and maintaining such temperature range until the decarboxylation is substantially complete.
2. The .method of making niacin from isocinchomeronic acid by the decarboxylation thereof by heat with recovery of the niacin produced, character zed by mixing isocinchomeronic-acid in water, and heating the mixture to a decarboxylating temperature range above C. and maintaining such temperature range until the decarboxylation is substantially complete.
3. The method of making niacin from isocinchomeronic acid by the decarboxylation thereof by heat with recovery of the niacin produced, characterized by mixing isocinchomeronic acid in heat transfer oil, and heating the mixture to a decarboxylating temperature range above 180 C. and maintaining such temperature range until the decarboxylation is substantially complete.
4. The method of making niacin from isocinchomeronic acid by the decarboxylation thereof by heat with recovery of the niacin produced, characterized by mixing isocinchomeronic acid in concentrated sulfuric acid, and heating the mixture to a decarboxylating temperature range above 180 C. and maintaining such temperature range until the decarboxylation is substantially complete.
5. The method of making niacin from isocinchomeronic acid by the decarboxylation thereof by heat with recovery of the niacin produced, characterized by mixing isocinchomeronic acid in cyclohexanone, and heating the mixture to a decarboxylating temperature range above 180 C. and maintaining such temperature range until the decarboxylation is substantially complete.
' References Cited in the file of this patent UNITED STATES PATENTS 2,280,040 Seibert et al. Apr. 14, 1942 2,389,065 Lee et a1 Nov. 13, 1945 2,524,957 Burrows et al. Oct. 10, 1950 FOREIGN PATENTS 234,588 Switzerland Feb. 1, 1945 OTHER REFERENCES Elderfield, Heterocyclic Compounds (1950), vol. 1, pp. 568-71.
Maier-Bode et al., Pyridin Und Seine Derivate (1934), p. 236.

Claims (1)

1. THE METHOD OF MAKING NIACIN FROM ISOCINCHOMERONIC ACID BY THE DECARBOXYLATION THEREOF BY HEAT WITH RECOVERY OF THE NIACIN PRODUCED, CHARACTERIZED BY MIXING ISOCINCHOMERONIC ACID IN THE NON-REACTIVE, SUBSTANTIALLY NON-CORROSIVE LIQUID VEHICLE SELECTED FROM THE GROUP CONSISTING OF WATER, HIGH TEMPERATURE HEAT TRANSFER OIL, CONCENTRATED SULFURIC ACID AND CYCLOHEXANONE, AND HEATING THE MIXTURE OF A DECARBOXYLATING TEMPERATURE RANGE ABOVE 180* C. AND MAINTAINING SUCH TEMPERATURE RANGE UNTIL THE DECARBOXYLATION IS SUBSTANTIALLY COMPLETE.
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2829144A (en) * 1955-04-14 1958-04-01 Warner Lambert Pharmaceutical Process for producing niacin from isocinchomeronic acid
US2834786A (en) * 1955-09-01 1958-05-13 Allied Chem & Dye Corp Process for preparing nicotinic acid
US2836601A (en) * 1956-02-09 1958-05-27 Warner Lambert Pharmaceutical Decarboxylation treatment
US2861077A (en) * 1955-10-07 1958-11-18 Robert S Aries Preparation of nicotinic acid esters
US2905688A (en) * 1954-10-04 1959-09-22 Abbott Lab Continuous process for production of nicotinic acid
US2996511A (en) * 1961-08-15 Process for the production of
US3081307A (en) * 1958-02-10 1963-03-12 Souren Z Avedikian Production of copper isocinchomeronate and isocinchomeronic acid

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2280040A (en) * 1939-10-13 1942-04-14 S M A Corp Preparation of nicotinic acid amide
CH234588A (en) * 1941-12-31 1944-10-15 Ig Farbenindustrie Ag Process for the production of nicotinic acid.
US2389065A (en) * 1941-09-24 1945-11-13 Hoffmann La Roche Process for the manufacture of nicotinic acid
US2524957A (en) * 1950-10-10 Isocinchomeronic acid by oxidation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2524957A (en) * 1950-10-10 Isocinchomeronic acid by oxidation
US2280040A (en) * 1939-10-13 1942-04-14 S M A Corp Preparation of nicotinic acid amide
US2389065A (en) * 1941-09-24 1945-11-13 Hoffmann La Roche Process for the manufacture of nicotinic acid
CH234588A (en) * 1941-12-31 1944-10-15 Ig Farbenindustrie Ag Process for the production of nicotinic acid.

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2996511A (en) * 1961-08-15 Process for the production of
US2905688A (en) * 1954-10-04 1959-09-22 Abbott Lab Continuous process for production of nicotinic acid
US2829144A (en) * 1955-04-14 1958-04-01 Warner Lambert Pharmaceutical Process for producing niacin from isocinchomeronic acid
US2834786A (en) * 1955-09-01 1958-05-13 Allied Chem & Dye Corp Process for preparing nicotinic acid
US2861077A (en) * 1955-10-07 1958-11-18 Robert S Aries Preparation of nicotinic acid esters
US2836601A (en) * 1956-02-09 1958-05-27 Warner Lambert Pharmaceutical Decarboxylation treatment
US3081307A (en) * 1958-02-10 1963-03-12 Souren Z Avedikian Production of copper isocinchomeronate and isocinchomeronic acid

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