Method for preparing calcium α-ketoglutarate

Abstract

Described herein are methods and processes for preparing the calcium salt of alpha-ketoglutarate.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 736,320, filed on September 25, 2018, under 35 U.S.C. §119(e), the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The invention described herein relates to methods and processes for preparing the calcium salt of alpha-ketoglutarate. Background Art

[0004] α-Ketoglutarate is an important biomolecule that is a key intermediate in the Krebs cycle, a nitrogen transporter, and a co-substance in molecular oxidation. The α-ketoglutarate anion plays a key role in metabolism, mainly in aerobic organisms. The calcium salt of α-ketoglutarate (Ca-AKG) is an important source of α-ketoglutarate anions.

[0005] The α-ketoglutarate anion (Formula 2, also known by the name of its acid 2-oxopentanedioic acid, 2-ketoglutaric acid, 2-oxoglutaric acid or oxoglutaric acid as depicted in Formula 1) is an intermediate in the Krebs cycle of eukaryotic organisms and is biosynthesized in these organisms from isocitrate (in the Krebs cycle process) or L-glutamate (via alanine aminotransferase). Both α-ketoglutarate and its corresponding acid are commercially available, either via preparation from fermentation cultures (see, e.g., US 2,776,926) or chemical synthesis from closely related compounds.

[0006]

[0007] Consistent with its role in energy production via the Krebs cycle, α-ketoglutarate is an important regulator of bioenergetics in cells and has been implicated as an inhibitor of the β subunit of ATP synthase and an indirect inhibitor of the kinase mTOR, a consequence of partial inhibition of the mitochondrial electron transport chain.

[0008] Known methods for synthesizing Ca-AKG from α-ketoglutarate require substantial purification of the final product, which results in increased time and cost of the overall process.Therefore, there is a need to find new methods for synthesizing Ca-AKG from α-ketoglutarate with reduced impurity formation. Summary of the invention

[0009] In certain embodiments, disclosed herein is a method for preparing calcium alpha-ketoglutarate, the method comprising a) contacting alpha-ketoglutaric acid with an alkali metal salt and water to form the corresponding di-salt of alpha-ketoglutaric acid; and b) contacting the di-salt of alpha-ketoglutaric acid with a calcium salt to form calcium alpha-ketoglutarate. Illustratively, the alkali metal salt is an alkali metal salt of an acid, wherein the conjugate acid of the alkali metal salt has at least one pKa from about 4 to about 12. Illustratively, the mixture of the alkali metal salt and water has a pH in the range of from about 5.0 to about 11.9. DETAILED DESCRIPTION

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the present disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention described herein, suitable methods and materials are described below. In the event of a conflict, this patent specification (including definitions) shall prevail. In addition, materials, methods and embodiments are illustrative only and are not intended to be limiting.

[0011] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without unacceptable toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0012] As used herein, "α-ketoglutarate" or "AKG" includes derivatives of α-ketoglutarate (e.g., derivatives described in MacKenzie et al. (2007) Mol Cell Biol 27(9):3282-3289), analogs of α-ketoglutarate (e.g., phosphonate analogs (e.g., those listed in Bunik et al. (2005) Biochemistry 44(31):10552-61), esters of α-ketoglutarate (e.g., dimethyl α-ketoglutarate and octyl α-ketoglutarate), and various species-specific analogs, e.g., human α-ketoglutarate, porcine α-ketoglutarate, murine α-ketoglutarate, bovine α-ketoglutarate, and the like.

[0013] α-Ketoglutarate (AKG)

[0014] Described herein is a method for preparing calcium alpha-ketoglutarate.

[0015] In certain aspects, the present invention provides compositions comprising compounds that are not approved by the FDA or are not generally recognized as safe (GRAS) for human consumption (e.g., alpha-ketoglutarate). These compounds may also be classified as such because they are: a) present in the FDA SCOGS database and are generally recognized as safe by the U.S. Food and Drug Administration; or b) derived from plants (e.g., fruits, vegetables, herbs) present in traditional diets and are therefore recognized by the scientific community as safe for consumption. In some embodiments, GRAS compounds are those that are suitable for human consumption without FDA approval.

[0016] In some embodiments, α-ketoglutaric acid is provided as a monolithium salt, a dilithium salt, a monosodium salt, a disodium salt, a monopotassium salt, a dipotassium salt, or a mixed salt of lithium, sodium or potassium, a calcium salt, or a zinc salt. In some embodiments, α-ketoglutaric acid is provided as a calcium salt. In other embodiments, the calcium salt of α-ketoglutaric acid is provided as an anhydrous salt, a monohydrate, or a dihydrate. In yet other embodiments, α-ketoglutaric acid is provided as a monovalent or divalent salt with other cations described in the USFDA Orange Book. These cations include calcium, diolamines, lithium, lysine, magnesium, meglumine, olamines, tromethamine, and zinc.

[0017] Method for preparing calcium α-ketoglutarate (Ca-AKG)

[0018] In an illustrative embodiment of the invention, described herein is a method for preparing calcium alpha-ketoglutarate, the method comprising:

[0019] a) contacting α-ketoglutaric acid with an alkali metal salt of the acid and water to form a double salt of α-ketoglutaric acid; and

[0020] b) contacting the double salt of α-ketoglutaric acid with a calcium salt and water to form calcium α-ketoglutarate;

[0021] The conjugate acid of the alkali metal salt has a pKa of from about 4 to about 12.

[0022] In another embodiment, described herein is a method for preparing calcium alpha-ketoglutarate, the method comprising:

[0023] a) contacting alpha-ketoglutaric acid with an alkali metal salt of the acid and water to form a solution having a pH in the range of from about 5 to about 11.9, thereby forming a double salt of alpha-ketoglutaric acid; and

[0024] b) contacting the double salt of α-ketoglutarate with a calcium salt and water to form calcium α-ketoglutarate.

[0025] Several illustrative embodiments of the present invention are described by the following enumerated clauses:

[0026] 1. A method for preparing calcium α-ketoglutarate, the method comprising:

[0027] a) contacting α-ketoglutaric acid with an alkali metal salt of an acid, wherein the conjugate acid of the alkali metal salt has at least one pKa from about 4 to about 12, thereby forming a di-salt of α-ketoglutaric acid; and

[0028] b) contacting the double salt of α-ketoglutarate with a calcium salt, thereby forming calcium α-ketoglutarate.

[0029] 2. The method of clause 1, wherein the conjugate of the acid has at least one pKa from about 5 to about 12.

[0030] 3. The method of clause 1, wherein the conjugate of the acid has at least one pKa from about 5.5 to about 12.

[0031] 4. The method of clause 1, wherein the conjugate of the acid has at least one pKa from about 5.5 to about 11.5.

[0032] 5. The method of clause 1, wherein the conjugate of the acid has at least one pKa from about 6 to about 11.5.

[0033] 6. The method of clause 1, wherein the conjugate of the acid has at least one pKa from about 6 to about 11.

[0034] 7. A method for preparing calcium α-ketoglutarate, the method comprising:

[0035] a) contacting alpha-ketoglutaric acid with an alkali metal salt of the acid and water to form a solution having a pH in the range of from about 5 to about 11.9, thereby forming a double salt of alpha-ketoglutaric acid; and

[0036] b) contacting the double salt of α-ketoglutarate with a calcium salt and water to form calcium α-ketoglutarate.

[0037] 8. The method of clause 7, wherein the pH is in the range of from about 5.3 to about 11.6.

[0038] 9. The method of any of the preceding clauses, wherein the alpha-ketoglutarate is mixed with water.

[0039] 10. The method of any of the preceding clauses, wherein the alpha-ketoglutarate and water mixture is prepared from or contains from about 0.05 to about 0.5 weight equivalents of alpha-ketoglutarate per weight equivalent of water.

[0040] 11. The method of any of the preceding clauses, wherein the alkali metal salt is mixed with water.

[0041] 12. The method of clause 11, wherein the alkali metal salt and water mixture has a pH in the range of from about 5 to about 11.9.

[0042] 13. The method of Clause 11, wherein the alkali metal salt and water mixture has a pH in the range of from about 5.2 to about 11.6.

[0043] 14. The method of Clause 11, wherein the alkali metal salt and water mixture has a pH in the range of from about 5.3 to about 11.5.

[0044] 15. The method of Clause 11, wherein the alkali metal salt and water mixture has a pH in the range of from about 5.3 to about 8.4.

[0045] 16. The method of any of the preceding clauses, wherein the alkali metal salt and water mixture is prepared from or contains from about 0.1 to about 0.35 weight equivalents of alkali metal salt per weight equivalent of water.

[0046] 17. The method of any of the preceding clauses, wherein the alkali metal salt is selected from the group consisting of lithium, sodium and potassium bicarbonates and carbonates, and combinations thereof.

[0047] 18. The method of any of the preceding clauses, wherein the alkali metal salt comprises sodium bicarbonate, sodium carbonate, or a mixture thereof.

[0048] 19. The method of any of the preceding clauses, wherein the alkali metal salt comprises sodium bicarbonate.

[0049] 20. The method of any of the preceding clauses, wherein the sodium bicarbonate and water mixture contains from about 0.2 to about 0.3 weight equivalents of sodium bicarbonate per weight equivalent of water.

[0050] 21. The method of clause 20, wherein the sodium bicarbonate and water mixture contains from about 0.23 to about 0.28 weight equivalents of sodium bicarbonate per weight equivalent of water.

[0051] 22. The method of any of the preceding clauses, wherein the alkali metal salt comprises sodium carbonate.

[0052] 23. The method of Clause 22, wherein the sodium carbonate and water mixture contains from about 0.05 to about 0.2 weight equivalents of sodium carbonate per weight equivalent of water.

[0053] 24. The method of Clause 22, wherein the sodium carbonate and water mixture contains from about 0.1 to about 0.2 weight equivalents of sodium carbonate per weight equivalent of water.

[0054] 25. The method of any of the preceding clauses, wherein the alkali metal salt is added to the alpha-ketoglutarate to form a mixture having a pH of at least about 6.5, optionally after a predetermined period of time.

[0055] 26. The method of Clause 25, wherein the alkali metal salt is added to the alpha-ketoglutaric acid to form a mixture having a pH of at least about 7.0, optionally after a predetermined period of time.

[0056] 27. The method of Clause 25, wherein the alkali metal salt is added to the alpha-ketoglutaric acid to form a mixture having a pH of at least about 7.5, optionally after a predetermined period of time.

[0057] 28. The method of Clause 25, wherein the alkali metal salt is added to the α-ketoglutarate to form a mixture having a pH of at least about 8, optionally after a predetermined period of time.

[0058] 29. The method of Clause 25, wherein the alkali metal salt is added to the alpha-ketoglutaric acid to form a mixture having a pH of at least about 8.5, optionally after a predetermined period of time.

[0059] 30. The method of Clause 25, wherein the alkali metal salt is added to the alpha-ketoglutaric acid to form a mixture having a pH from about 6.5 to about 9, optionally after a predetermined period of time.

[0060] 31. The method of Clause 25, wherein the alkali metal salt is added to the alpha-ketoglutaric acid to form a mixture having a pH from about 6.5 to about 8.5, optionally after a predetermined period of time.

[0061] 32. The method of any of the preceding clauses, wherein the alpha-ketoglutaric acid is from about 0.5 to about 3 weight equivalents per weight equivalent of the alkali metal salt.

[0062] 33. The method of clause 32, wherein the alpha-ketoglutaric acid is from about 0.7 to about 0.9 weight equivalent per weight equivalent of sodium bicarbonate.

[0063] 34. The method of clause 32, wherein the alpha-ketoglutarate is from about 0.74 to about 0.88 weight equivalents per weight equivalent of sodium bicarbonate.

[0064] 35. The method of any of the preceding clauses, wherein the alpha-ketoglutarate is from about 1.0 to about 2.8 weight equivalents per weight equivalent of sodium carbonate.

[0065] 36. The method of Clause 35, wherein the alpha-ketoglutaric acid is from about 1.1 to about 2.8 weight equivalents per weight equivalent of sodium carbonate.

[0066] 37. The method of Clause 35, wherein the alpha-ketoglutaric acid is from about 1.1 to about 2.5 weight equivalents per weight equivalent of sodium carbonate.

[0067] 38. The method of Clause 35, wherein the alpha-ketoglutaric acid is from about 1.1 to about 1.2 weight equivalents per weight equivalent of sodium carbonate.

[0068] 39. The method of any of the preceding clauses, wherein the alpha-ketoglutarate is contacted with the sodium bicarbonate and water mixture at about 50°C or less.

[0069] 40. The method of Clause 39, wherein the alpha-ketoglutaric acid is contacted with the sodium bicarbonate and water mixture at about 40°C or less.

[0070] 41. The method of Clause 39, wherein the alpha-ketoglutaric acid is contacted with the sodium bicarbonate and water mixture at about 35°C or less.

[0071] 42. The method of Clause 39, wherein the alpha-ketoglutaric acid is contacted with the sodium bicarbonate and water mixture at about 30°C or less.

[0072] 43. The method of Clause 39, wherein the alpha-ketoglutaric acid is contacted with the sodium bicarbonate and water mixture at about 25°C or less.

[0073] 44. The method of Clause 39, wherein the alpha-ketoglutaric acid is contacted with the sodium bicarbonate and water mixture at about 10°C to about 50°C.

[0074] 45. The method of Clause 39, wherein the alpha-ketoglutaric acid is contacted with the sodium bicarbonate and water mixture at about 10°C to about 40°C.

[0075] 46. ​​The method of Clause 39, wherein the alpha-ketoglutaric acid is contacted with the sodium bicarbonate and water mixture at about 10°C to about 35°C.

[0076] 47. The method of Clause 39, wherein the alpha-ketoglutaric acid is contacted with the sodium bicarbonate and water mixture at about 10°C to about 30°C.

[0077] 48. The method of Clause 39, wherein the alpha-ketoglutaric acid is contacted with the sodium bicarbonate and water mixture at about 10°C to about 25°C.

[0078] 49. The method of any of the preceding clauses, wherein the alpha-ketoglutarate and the sodium bicarbonate and water mixture are stirred for at least about 30 minutes.

[0079] 50. The method of Clause 49, wherein the alpha-ketoglutaric acid and the sodium bicarbonate and water mixture are stirred for at least about 1 hour.

[0080] 51. The method of Clause 49, wherein the alpha-ketoglutaric acid and the sodium bicarbonate and water mixture are stirred for at least about 2 hours.

[0081] 52. The method of Clause 49, wherein the alpha-ketoglutaric acid and the sodium bicarbonate and water mixture are stirred for at least about 3 hours.

[0082] 53. The method of Clause 49, wherein the alpha-ketoglutaric acid and the sodium bicarbonate and water mixture are stirred for at least about 4 hours.

[0083] 54. The method of Clause 49, wherein the alpha-ketoglutaric acid and the sodium bicarbonate and water mixture are stirred for about 30 minutes to about 6 hours or less.

[0084] 55. The method of Clause 49, wherein the alpha-ketoglutaric acid and the sodium bicarbonate and water mixture are stirred for about 1 hour to about 6 hours or less.

[0085] 56. The method of Clause 49, wherein the alpha-ketoglutaric acid and the sodium bicarbonate and water mixture are stirred for about 2 hours to about 6 hours or less.

[0086] 57. The method of any of the preceding clauses, wherein the calcium salt is selected from the group consisting of calcium formate, calcium acetate, and calcium chloride.

[0087] 58. The method of Clause 57, wherein the calcium salt is calcium chloride.

[0088] 59. The method of any of the preceding clauses, wherein the calcium salt is mixed with water.

[0089] 60. The method of Clause 59, wherein the calcium salt and water mixture is prepared from or contains from about 0.1 to about 1 weight equivalent of the calcium salt per weight equivalent of water.

[0090] 61. The method of Clause 59, wherein the calcium chloride and water mixture contains from about 0.1 to about 0.6 weight equivalents of the calcium chloride per weight equivalent of water.

[0091] 62. The method of Clause 59, wherein the calcium chloride and water mixture contains from about 0.2 to about 0.5 weight equivalents of the calcium chloride per weight equivalent of water.

[0092] 63. The method of Clause 59, wherein the calcium chloride and water mixture contains from about 0.23 to about 0.4 weight equivalents of the calcium chloride per weight equivalent of water.

[0093] 64. The method of Clause 59, wherein the calcium chloride and water mixture contains from about 0.2 to about 0.5 weight equivalents of the calcium chloride per weight equivalent of water.

[0094] 65. The method of any of the preceding clauses, wherein the calcium salt is from 0.5 to 2 weight equivalents per weight equivalent of alpha-ketoglutaric acid.

[0095] 66. The method of clause 64, wherein the calcium salt is from 0.75 to 2 weight equivalents per weight equivalent of alpha-ketoglutaric acid.

[0096] 67. The method of clause 64, wherein the calcium chloride is from about 0.75 to about 1.35 weight equivalents per weight equivalent of alpha-ketoglutaric acid.

[0097] 68. The method of Clause 64, wherein the calcium chloride is from about 0.9 to about 1.1 weight equivalents per weight equivalent of alpha-ketoglutaric acid.

[0098] 69. The method of any of the preceding clauses, wherein the double salt of alpha-ketoglutarate, such as disodium alpha-ketoglutarate, is contacted with the calcium salt and water mixture at about 40°C to about 90°C.

[0099] 70. The process of clause 69, wherein the dialkali metal salt of alpha-ketoglutarate such as disodium alpha-ketoglutarate and the calcium salt and water mixture are stirred at about 65°C to about 75°C.

[0100] 71. The method of any of the preceding clauses, wherein the double alkali metal salt of alpha-ketoglutarate, such as disodium alpha-ketoglutarate and the calcium salt and water mixture are stirred for at least about 30 min.

[0101] 72. The method of clause 71, wherein the dialkali metal salt of alpha-ketoglutarate, such as disodium alpha-ketoglutarate and the calcium salt and water mixture are stirred for at least about 1 hour.

[0102] 73. The method of clause 71, wherein the dialkali metal salt of alpha-ketoglutarate, such as disodium alpha-ketoglutarate and the calcium salt and water mixture are stirred for at least about 2 hours.

[0103] 74. The method of clause 71, wherein the dialkali metal salt of alpha-ketoglutarate, such as disodium alpha-ketoglutarate and the calcium salt and water mixture are stirred for at least about 4 hours.

[0104] 75. The method of clause 71, wherein the dialkali metal salt of alpha-ketoglutarate, such as disodium alpha-ketoglutarate and the calcium salt and water mixture are stirred for at least about 5 hours.

[0105] 76. The method of clause 71, wherein the dialkali metal salt of alpha-ketoglutarate, such as disodium alpha-ketoglutarate and the calcium salt and water mixture are stirred for about 30 minutes to about 5 hours or less.

[0106] 77. The method of clause 71, wherein the dialkali metal salt of alpha-ketoglutarate, such as disodium alpha-ketoglutarate and the calcium salt and water mixture are stirred for about 1 hour to about 5 hours or less.

[0107] 78. The method of clause 71, wherein the dialkali metal salt of alpha-ketoglutarate, such as disodium alpha-ketoglutarate and the calcium salt and water mixture are stirred for about 2 hours to about 5 hours or less.

[0108] 79. The method of any of the preceding clauses, further comprising drying the calcium alpha-ketoglutarate.

[0109] 80. The method of any of the preceding clauses, further comprising drying the calcium alpha-ketoglutarate to a moisture content of about 20% to about 5%.

[0110] 81. The method of Clause 80, comprising drying the calcium alpha-ketoglutarate to a moisture content of about 15% to about 5%.

[0111] 82. The method of Clause 80, comprising drying the calcium alpha-ketoglutarate to a moisture content of about 15% to about 8%.

[0112] 83. The method of Clause 80, comprising drying the calcium alpha-ketoglutarate to a moisture content of about 12% to about 8%.

[0113] 84. The method of Clause 80, comprising drying the calcium alpha-ketoglutarate to a moisture content of about 10% to about 8%.

[0114] 85. The method of any of the preceding clauses, further comprising drying the calcium alpha-ketoglutarate, wherein the dried calcium alpha-ketoglutarate is less than 50% calcium alpha-ketoglutarate dihydrate.

[0115] 86. The method of any of the preceding clauses, further comprising drying the calcium alpha-ketoglutarate, wherein the dried calcium alpha-ketoglutarate is at least 50% calcium alpha-ketoglutarate monohydrate.

[0116] 87. A method for preparing calcium alpha-ketoglutarate, the method comprising:

[0117] a) contacting α-ketoglutaric acid with a solution of sodium bicarbonate in water to form disodium α-ketoglutarate; and

[0118] b) contacting disodium α-ketoglutarate with a solution of aqueous calcium chloride to form calcium α-ketoglutarate;

[0119] wherein the sodium bicarbonate solution is prepared from about 0.27 weight equivalents of sodium bicarbonate per weight equivalent of water;

[0120] wherein the α-ketoglutaric acid is about 0.74 weight equivalent per weight equivalent of sodium bicarbonate;

[0121] wherein the α-ketoglutaric acid is contacted with the sodium bicarbonate aqueous solution at about 10°C to about 35°C, or at about 10°C to about 25°C;

[0122] wherein the solution of α-ketoglutaric acid and sodium bicarbonate water is stirred at about 10° C. to about 35° C., or at about 10° C. to about 25° C. for about 2 hours;

[0123] wherein the calcium chloride solution is prepared from about 0.2 to about 0.5 weight equivalent of the calcium chloride per weight equivalent of water;

[0124] wherein the calcium chloride is about 0.95 weight equivalent per weight equivalent of α-ketoglutaric acid;

[0125] The α-ketoglutarate disodium and calcium chloride solutions are stirred at 65° C. to 70° C. for about 4 hours.

[0126] 88. A method for preparing calcium alpha-ketoglutarate, the method comprising:

[0127] a) contacting α-ketoglutarate with a solution of sodium carbonate and water to form disodium α-ketoglutarate; and

[0128] b) contacting disodium α-ketoglutarate with a solution of aqueous calcium chloride to form calcium α-ketoglutarate;

[0129] wherein the sodium carbonate solution is prepared from about 0.18 weight equivalent of sodium carbonate per weight equivalent of water;

[0130] wherein the α-ketoglutaric acid is about 1.14 weight equivalents per weight equivalent of sodium carbonate;

[0131] wherein the α-ketoglutaric acid is contacted with the solution of sodium carbonate and water at about 10°C to about 35°C, or at about 10°C to about 25°C;

[0132] wherein the α-ketoglutaric acid and the solution of sodium carbonate and water are stirred at about 10°C to about 35°C, or at about 10°C to about 25°C for 2 hours;

[0133] wherein the calcium chloride solution is prepared from about 0.2 to about 0.5 weight equivalent of said calcium chloride per weight equivalent of water;

[0134] wherein the calcium chloride is about 0.95 weight equivalent per weight equivalent of α-ketoglutaric acid;

[0135] The solution of disodium α-ketoglutarate, calcium salt and water was stirred at 65°C to 70°C for about 4 hours.

[0136] It should be understood that all weight equivalents of components, reactants, reagents, solvents and the like described herein are descriptions of corresponding molar equivalents, each of which is obtained from the molecular weights of these components, reactants, reagents, solvents and the like. In addition, it should be understood that certain weight equivalents such as the weight equivalents of a specific alkali metal salt and water can be converted to the corresponding weight equivalents of the alternative alkali metal salt and water by accounting for the different molecular weights of the specific alkali metal salt and the alternative alkali metal salt. It should also be understood that the same conversion between the specific weight equivalents of α-ketoglutaric acid and water, or the weight equivalents of α-ketoglutaric acid and alkali metal salts, or the weight equivalents of calcium salts and water, or the weight equivalents of calcium salts and α-ketoglutaric acid and alternatives, respectively, is calculated by accounting for different molecular weights in each case.

[0137] For example, it should be understood that all weight equivalents of the alkali metal salts of the acids described herein can also be expressed as molar equivalents, such as expressed in molar ratios or molar concentrations. Illustratively, in the case where the water mixture contains about 0.1 to about 0.35 weight equivalents of sodium bicarbonate per weight equivalent of water, corresponding to about 1.2 to about 4.2 millimolar equivalents of sodium bicarbonate or sodium ions per mL of water, or about 1.2 to about 4.2 millimolar sodium ion concentration ranges. It should be further understood that the same range of millimolar equivalents or millimolar concentrations can be used with other alkali metal salts of acids or mixtures thereof (such as lithium bicarbonate, lithium carbonate, sodium carbonate, potassium bicarbonate, potassium carbonate and the like described herein). It should be further understood that the same range of millimolar equivalents or millimolar concentrations used with other alkali metal salts of acids (such as lithium bicarbonate, lithium carbonate, sodium carbonate, potassium bicarbonate, potassium carbonate and the like described herein) can be expressed as corresponding weight equivalents.

[0138] Illustratively, the methods described herein include contacting alpha-ketoglutaric acid with an aqueous mixture of potassium bicarbonate, wherein the aqueous mixture contains from about 1.2 to about 4.2 millimolar equivalents of potassium bicarbonate or potassium ions per mL of water, or a potassium ion concentration range of about 1.2 to about 4.2 millimolar. The methods described herein, expressed in terms of weight equivalents, include contacting alpha-ketoglutaric acid with an aqueous mixture of potassium bicarbonate, wherein the aqueous mixture contains from about 0.12 to about 0.42 weight equivalents of potassium bicarbonate per weight equivalent of water.

[0139] Illustratively, the methods described herein include contacting an aqueous mixture of alpha-ketoglutaric acid with sodium carbonate or potassium carbonate, wherein the aqueous mixture contains from about 1.2 to about 4.2 millimolar equivalents of sodium or potassium ions per mL of water, or a sodium or potassium ion concentration range of about 1.2 to about 4.2 millimolar. It should be understood that sodium carbonate includes two sodium ions, and thus the methods described herein expressed in weight equivalents include contacting an aqueous mixture of alpha-ketoglutaric acid and sodium carbonate, wherein the aqueous mixture contains from about 0.06 to about 0.22 weight equivalents of sodium carbonate per weight equivalent of water. It should also be understood that potassium carbonate includes two potassium ions, and thus the methods described herein expressed in weight equivalents include contacting an aqueous mixture of alpha-ketoglutaric acid and potassium carbonate, wherein the aqueous mixture contains from about 0.08 to about 0.29 weight equivalents of potassium carbonate per weight equivalent of water.

[0140] Alkali metal salts

[0141] In some embodiments, the alkali metal salt is selected from lithium bicarbonate, lithium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, and combinations thereof. In some embodiments, the alkali metal salt comprises sodium bicarbonate. In some embodiments, the alkali metal salt comprises sodium carbonate. In some embodiments, the alkali metal salt is sodium bicarbonate. In some embodiments, the alkali metal salt is sodium carbonate.

[0142] Alkali metal salt to water ratio

[0143] In some embodiments, the alkali metal salt and water are added as a mixture. In some embodiments, the alkali metal salt and water mixture contains from 0.1 to 0.35 weight equivalents of alkali metal salt per weight equivalent of water.

[0144] In some embodiments, sodium bicarbonate and water are added as a mixture. In some embodiments, the sodium bicarbonate and water mixture contains from 0.1 to 0.3 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains from 0.1 to 0.25 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains from 0.15 to 0.3 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains from 0.15 to 0.25 weight equivalents of sodium bicarbonate per weight equivalent of water.

[0145] In some embodiments, the sodium bicarbonate and water mixture contains from 0.2 to 0.3 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains from 0.2 to 0.25 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.15 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.16 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.17 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.18 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.19 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.2 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.21 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.22 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.23 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.24 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.25 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.26 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.27 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.28 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.29 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.3 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.31 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.32 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.33 weight equivalents of sodium bicarbonate per weight equivalent of water. In some embodiments, the sodium bicarbonate and water mixture contains 0.34 weight equivalents of sodium bicarbonate per weight equivalent of water.In some embodiments, the sodium bicarbonate and water mixture contains 0.35 weight equivalents of sodium bicarbonate per weight equivalent of water.

[0146] In some embodiments, sodium carbonate and water are added as a mixture. In some embodiments, the sodium carbonate and water mixture contains sodium carbonate from about 0.05 to about 0.35 weight equivalents of water per weight equivalent. In some embodiments, the sodium carbonate and water mixture contains sodium carbonate from about 0.05 to about 0.2 weight equivalents of water per weight equivalent. In some embodiments, the sodium carbonate and water mixture contains sodium carbonate from 0.1 to 0.35 weight equivalents of water per weight equivalent. In some embodiments, the sodium carbonate and water mixture contains sodium carbonate from 0.1 to 0.25 weight equivalents of water per weight equivalent. In some embodiments, the sodium carbonate and water mixture contains sodium carbonate from 0.15 to 0.3 weight equivalents of water per weight equivalent. In some embodiments, the sodium carbonate and water mixture contains sodium carbonate from 0.15 to 0.25 weight equivalents of water per weight equivalent. In some embodiments, the sodium carbonate and water mixture contains from 0.2 to 0.3 weight equivalents of sodium carbonate per weight equivalent of water. In some embodiments, the sodium carbonate and water mixture contains from 0.2 to 0.25 weight equivalents of sodium carbonate per weight equivalent of water. In some embodiments, the sodium carbonate and water mixture contains 0.15 weight equivalents of sodium carbonate per weight equivalent of water. In some embodiments, the sodium carbonate and water mixture contains 0.16 weight equivalents of sodium carbonate per weight equivalent of water. In some embodiments, the sodium carbonate and water mixture contains 0.17 weight equivalents of sodium carbonate per weight equivalent of water. In some embodiments, the sodium carbonate and water mixture contains 0.18 weight equivalents of sodium carbonate per weight equivalent of water. In some embodiments, the sodium carbonate and water mixture contains 0.19 weight equivalents of sodium carbonate per weight equivalent of water. In some embodiments, the sodium carbonate and water mixture contains 0.2 weight equivalents of sodium carbonate per weight equivalent of water. In some embodiments, the sodium carbonate and water mixture contains 0.21 weight equivalents of sodium carbonate per weight equivalent of water. In some embodiments, the sodium carbonate and water mixture contains 0.22 weight equivalents of sodium carbonate per weight equivalent of water. In some embodiments, the sodium carbonate and water mixture contains 0.23 weight equivalents of sodium carbonate per weight equivalent of water. In some embodiments, the sodium carbonate and water mixture contains 0.24 weight equivalents of sodium carbonate per weight equivalent of water. In some embodiments, the sodium carbonate and water mixture contains 0.25 weight equivalents of sodium carbonate per weight equivalent of water.

[0147] Ratio of α-ketoglutarate to alkali metal salt

[0148] In some embodiments, the alpha-ketoglutaric acid is from about 0.5 to about 3 weight equivalents per weight equivalent of the alkali metal salt. In some embodiments, the alpha-ketoglutaric acid is from 0.5 to 0.9 weight equivalents per weight equivalent of the alkali metal salt.

[0149] In some embodiments, the alpha-ketoglutaric acid is from 0.5 to 0.9 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.6 to 0.9 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.7 to 0.9 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.5 to 0.8 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.6 to 0.8 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.7 to 0.8 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.7 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.71 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.72 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.73 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.74 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.75 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.76 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.77 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.78 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.79 weight equivalents per weight equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.8 weight equivalents per weight equivalent of sodium bicarbonate.

[0150] In some embodiments, the alpha-ketoglutaric acid is from 0.33 to 0.5 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.33 to 0.45 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.35 to 0.45 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.36 to 0.45 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.37 to 0.45 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.38 to 0.45 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.39 to 0.45 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.4 to 0.45 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.35 to 0.44 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.36 to 0.44 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.37 to 0.44 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.38 to 0.44 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.39 to 0.44 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.4 to 0.44 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.35 to 0.43 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.36 to 0.43 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.37 to 0.43 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.38 to 0.43 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.39 to 0.43 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.4 to 0.43 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.35 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutarate is 0.36 molar equivalent per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutarate is 0.37 molar equivalent per molar equivalent of sodium bicarbonate.In some embodiments, the alpha-ketoglutaric acid is 0.38 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.39 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.4 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.41 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.42 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.43 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.44 molar equivalents per molar equivalent of sodium bicarbonate. In some embodiments, the alpha-ketoglutaric acid is 0.45 molar equivalents per molar equivalent of sodium bicarbonate.

[0151] In some embodiments, the α-ketoglutaric acid is from 1 to 2.8 weight equivalents per weight equivalent of alkali metal salt. In some embodiments, the α-ketoglutaric acid is from 1 to 2.8 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is from 0.9 to 1.4 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is from 1 to 1.4 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is from 1.1 to 1.4 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is from 0.9 to 1.3 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is from 1 to 1.3 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is from 1.1 to 1.3 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is from 0.9 to 1.2 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is from 1 to 1.2 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is from 1.1 to 1.2 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is 1.05 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is 1.06 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is 1.07 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is 1.08 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is 1.09 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the α-ketoglutaric acid is 1.1 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 1.11 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 1.12 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 1.13 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 1.14 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 1.15 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 1.16 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 1.17 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 1.18 weight equivalents per weight equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 1.19 weight equivalents per weight equivalent of sodium carbonate.In some embodiments, the alpha-ketoglutaric acid is 1.20 weight equivalents per weight equivalent of sodium carbonate.

[0152] In some embodiments, the alpha-ketoglutaric acid is from 0.5 to 1 molar equivalent per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.6 to 1 molar equivalent per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.7 to 1 molar equivalent per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.8 to 1 molar equivalent per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.5 to 0.9 molar equivalent per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.6 to 0.9 molar equivalent per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.7 to 0.9 molar equivalent per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is from 0.8 to 0.9 molar equivalent per molar equivalent of sodium carbonate.

[0153] In some embodiments, the alpha-ketoglutaric acid is 0.75 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.76 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.77 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.78 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.79 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.8 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.81 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.82 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.83 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.84 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.85 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.86 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.87 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.88 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.89 molar equivalents per molar equivalent of sodium carbonate. In some embodiments, the alpha-ketoglutaric acid is 0.9 molar equivalents per molar equivalent of sodium carbonate.

[0154] Contact temperature of alkali metal salt and α-ketoglutaric acid

[0155] In some embodiments, the alpha-ketoglutaric acid is contacted with an alkali metal salt at about 50°C or less, about 40°C or less, about 35°C or less, about 30°C or less, or about 25°C or less. In some embodiments, the alpha-ketoglutaric acid is contacted with an alkali metal salt at a temperature in the range of from about 10°C to about 50°C, from about 10°C to about 40°C, from about 10°C to about 35°C, from about 10°C to about 30°C, from about 10°C to about 25°C.

[0156] In some embodiments, α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 10°C to 50°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 10°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 10°C to 35°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 10°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 10°C to 25°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 15°C to 50°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 15°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 15°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 20°C to 50°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 20°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 20°C to 35°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 20°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 20°C to 25°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 25°C to 50°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 25°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 25°C to 35°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 25°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 20°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 21°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 22°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 23°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 24°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 25°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 26°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 27°C. In some embodiments, the alpha-ketoglutarate is contacted with a sodium bicarbonate and water mixture at 28°C.In some embodiments, the alpha-ketoglutarate is contacted with the sodium bicarbonate and water mixture at 29° C. In some embodiments, the alpha-ketoglutarate is contacted with the sodium bicarbonate and water mixture at 30° C.

[0157] In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 10°C to 50°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 10°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 10°C to 35°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 10°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 10°C to 25°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 15°C to 50°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 15°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 15°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 20°C to 50°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 20°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 20°C to 35°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 20°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 20°C to 25°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 25°C to 50°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 25°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 25°C to 35°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 25°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 20°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 21°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 22°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 23°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 24°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 25°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 26°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 27°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 28°C. In some embodiments, the alpha-ketoglutarate is contacted with a sodium carbonate and water mixture at 29°C.In some embodiments, the alpha-ketoglutarate is contacted with a sodium carbonate and water mixture at 30°C.

[0158] Contact time of α-ketoglutaric acid and alkali metal salt

[0159] In some embodiments, the alpha-ketoglutaric acid and alkali metal salt and water mixture is stirred for at least 30 min, at least about 1 hour, at least about 2 hours, at least about 3 hours, or at least about 4 hours.

[0160] In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture is stirred for 30 minutes. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture is stirred for 1 hour. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture is stirred for 2 hours. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture is stirred for 3 hours. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture is stirred for 4 hours. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture is stirred for 6 hours. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture is stirred for 8 hours. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture is stirred for 10 hours. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture is stirred for 12 hours.

[0161] In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred for 30 minutes. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred for 1 hour. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred for 2 hours. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred for 3 hours. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred for 4 hours. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred for 6 hours. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred for 8 hours. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred for 10 hours. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred for 12 hours.

[0162] Stirring temperature of α-ketoglutaric acid and alkali metal salt

[0163] In some embodiments, alpha-ketoglutaric acid is stirred with an alkali metal salt at about 50°C or less, about 40°C or less, about 35°C or less, about 30°C or less, or about 25°C or less.

[0164] In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture are stirred at 10°C to 50°C. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture are stirred at 10°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with sodium bicarbonate and water mixture at 10°C to 35°C. In some embodiments, the α-ketoglutaric acid is contacted with sodium bicarbonate and water mixture at 10°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with sodium bicarbonate and water mixture at 10°C to 25°C. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture are stirred at 15°C to 50°C. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture are stirred at 15°C to 40°C. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture are stirred at 15°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 20°C to 50°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 20°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 20°C to 35°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 20°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 20°C to 25°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 25°C to 50°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 25°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 25°C to 35°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium bicarbonate and water mixture at 25°C to 30°C. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture are stirred at 20°C. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture are stirred at 21°C. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture are stirred at 22°C. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture are stirred at 23°C. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture are stirred at 24°C. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture are stirred at 25°C. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture are stirred at 26°C. In some embodiments, the α-ketoglutaric acid and sodium bicarbonate and water mixture are stirred at 27°C. In some embodiments, the alpha-ketoglutaric acid and sodium bicarbonate and water mixture is stirred at 28°C.In some embodiments, the alpha-ketoglutaric acid and sodium bicarbonate and water mixture is stirred at 29° C. In some embodiments, the alpha-ketoglutaric acid and sodium bicarbonate and water mixture is stirred at 30° C.

[0165] In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 10°C to 50°C. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 10°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 10°C to 35°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 10°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 10°C to 25°C. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 15°C to 50°C. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 15°C to 40°C. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 15°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 20°C to 50°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 20°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 20°C to 35°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 20°C to 30°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 20°C to 25°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 25°C to 50°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 25°C to 40°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 25°C to 35°C. In some embodiments, the α-ketoglutaric acid is contacted with a sodium carbonate and water mixture at 25°C to 30°C. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 20°C. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 21°C. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 22°C. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 23°C. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 24°C. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 25°C. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 26°C. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 27°C. In some embodiments, the α-ketoglutaric acid and sodium carbonate and water mixture are stirred at 28°C. In some embodiments, the alpha-ketoglutaric acid and sodium carbonate and water mixture is stirred at 29°C.In some embodiments, the alpha-ketoglutaric acid and sodium carbonate and water mixture is stirred at 30°C.

[0166] pH

[0167] In some embodiments, the alpha-ketoglutaric acid and alkali metal salt and water mixture is stirred until the reaction pH is at least about 6, at least about 6.5, at least about 7, at least about 7.5, at least about 8, at least about 8.5, at least about 9, or in the range of from about 6.5 to about 9.

[0168] In some embodiments, the alpha-ketoglutaric acid and sodium bicarbonate and water mixture is stirred until the reaction pH is from 6 to 10. In some embodiments, the pH is from 7 to 9. In some embodiments, the pH is from 7 to 8. In some embodiments, the pH is 7.4 ± 0.4. In some embodiments, the pH is 7.1. In some embodiments, the pH is 7.2. In some embodiments, the pH is 7.3. In some embodiments, the pH is 7.4. In some embodiments, the pH is 7.5. In some embodiments, the pH is 7.6. In some embodiments, the pH is 7.7. In some embodiments, the pH is 7.8. In some embodiments, the pH is 7.9. In some embodiments, the pH is 8.

[0169] In some embodiments, the alpha-ketoglutaric acid and sodium carbonate and water mixture is stirred until the reaction pH is from 6 to 10. In some embodiments, the pH is from 7 to 9. In some embodiments, the pH is from 7 to 8. In some embodiments, the pH is 7.4 ± 0.4. In some embodiments, the pH is 7.1. In some embodiments, the pH is 7.2. In some embodiments, the pH is 7.3. In some embodiments, the pH is 7.4. In some embodiments, the pH is 7.5. In some embodiments, the pH is 7.6. In some embodiments, the pH is 7.7. In some embodiments, the pH is 7.8. In some embodiments, the pH is 7.9. In some embodiments, the pH is 8.

[0170] Calcium salt

[0171] In some embodiments, the calcium salt is selected from commercially available calcium salts, including but not limited to calcium formate, calcium acetate, calcium chloride and the like, and mixtures thereof. In some embodiments, the calcium salt is selected from the group consisting of calcium acetate and calcium chloride. In some embodiments, the calcium salt is calcium acetate. In some embodiments, the calcium salt is calcium chloride.

[0172] Calcium salt to water ratio

[0173] In some embodiments, the calcium salt and water are added as a mixture. In some embodiments, the calcium salt and water mixture contains from 0.1 to 1 weight equivalent of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains from 0.1 to 0.8 weight equivalent of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains from 0.1 to 0.6 weight equivalent of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains from 0.1 to 0.5 weight equivalent of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains from 0.3 to 1 weight equivalent of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains from 0.3 to 0.8 weight equivalent of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains from 0.3 to 0.6 weight equivalent of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains from 0.3 to 0.5 weight equivalents of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains 0.3 weight equivalents of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains 0.32 weight equivalents of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains 0.34 weight equivalents of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains 0.36 weight equivalents of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains 0.38 weight equivalents of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains 0.4 weight equivalents of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains 0.42 weight equivalents of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains 0.44 weight equivalents of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains 0.46 weight equivalents of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains 0.48 weight equivalents of the calcium salt per weight equivalent of water. In some embodiments, the calcium salt and water mixture contains 0.5 weight equivalents of the calcium salt per weight equivalent of water.

[0174] Ratio of calcium salt to α-ketoglutarate

[0175] In some embodiments, the calcium salt is from 0.5 to 2 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is from 0.6 to 1.7 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is from 0.7 to 1.4 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is from 0.8 to 1.2 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is from 0.9 to 1.1 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.8 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.85 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.86 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.87 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.88 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.89 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.9 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.91 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.92 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.93 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.94 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.95 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.96 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.97 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.98 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 0.99 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1 weight equivalent per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.01 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.02 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.03 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.04 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.05 weight equivalents per weight equivalent of alpha-ketoglutaric acid.In some embodiments, the calcium salt is 1.06 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.07 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.08 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.09 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.1 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.2 weight equivalents per weight equivalent of alpha-ketoglutaric acid.

[0176] In some embodiments, the calcium salt is from 1 to 3 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is from 1 to 2 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is from 1 to 1.75 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is from 1 to 1.5 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is from 1.1 to 1.75 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is from 1.1 to 1.5 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is from 1.1 to 1.3 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is from 1.2 to 1.75 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is from 1.2 to 1.5 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is from 1.2 to 1.3 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1 molar equivalent per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.1 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.15 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.16 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.17 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.18 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.19 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.2 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.21 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.22 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.23 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.24 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.25 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.26 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.27 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.28 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.29 molar equivalents per molar equivalent of alpha-ketoglutaric acid.In some embodiments, the calcium salt is 1.3 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.31 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.32 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.33 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.34 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.35 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.36 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.37 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.38 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.39 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.4 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.41 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.42 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.43 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.44 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.45 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.5 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.6 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.7 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.8 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 1.9 molar equivalents per molar equivalent of alpha-ketoglutaric acid. In some embodiments, the calcium salt is 2 molar equivalents per molar equivalent of alpha-ketoglutaric acid.

[0177] Contact temperature of AKG double salt and calcium salt

[0178] In some embodiments, alpha-ketoglutarate is contacted with the calcium salt at about 40°C or above, about 90°C or below, or in the range from about 40°C to about 90°C, or about 65°C to about 75°C.

[0179] In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 40°C to 90°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 50°C to 80°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 60°C to 75°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 65°C to 70°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 60°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 61°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 62°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 63°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 64°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 65°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 66°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 67°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 68°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 69°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 70°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 71°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 72°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 73°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 74°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 75°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 76°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 78°C. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred at 80°C.

[0180] Contact time of AKG disodium and Ca salt

[0181] In some embodiments, the double alkali metal salt and calcium salt of alpha-ketoglutarate and water mixture is stirred for at least 30 min, at least about 1 hour, at least about 2 hours, at least about 3 hours, or at least about 4 hours.

[0182] In some embodiments, the α-ketoglutarate disodium and calcium salt and water mixture are stirred for 30min to 24 hours. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred for 1 hour to 12 hours. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred for 4 hours to 9 hours. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred for 5 hours to 6 hours. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred for 4 hours. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred for 5 hours. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred for 6 hours. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred for 8 hours. In some embodiments, the α-ketoglutarate disodium and the calcium salt and water mixture are stirred for 10 hours. In some embodiments, the disodium alpha-ketoglutarate and the calcium salt and water mixture are stirred for 12 hours.

[0183] Additional steps of filtering, washing and drying

[0184] In some embodiments, the method further comprises isolating the calcium alpha-ketoglutarate. In some embodiments, the separated calcium alpha-ketoglutarate is washed with water. In some embodiments, the separated calcium alpha-ketoglutarate is exposed to a vacuum source. In some embodiments, the separated calcium alpha-ketoglutarate is exposed to a heat source. In some embodiments, the heat source comprises a hot air stream, an oven, or an IR lamp.

[0185] Drying temperature

[0186] In some embodiments, the separated calcium alpha-ketoglutarate is heated to a temperature of at least 30°C to at least 150°C. In some embodiments, the separated calcium alpha-ketoglutarate is heated to a temperature of at least 50°C to at least 150°C. In some embodiments, the separated calcium alpha-ketoglutarate is heated to a temperature of at least 60°C to at least 100°C. In some embodiments, the separated calcium alpha-ketoglutarate is heated to a temperature of at least 70°C to at least 90°C. In some embodiments, the separated calcium alpha-ketoglutarate is heated to a temperature of at least 80°C to at least 85°C. In some embodiments, the separated calcium alpha-ketoglutarate is heated to a temperature of at least 50°C to at least 60°C. In some embodiments, the separated calcium alpha-ketoglutarate is heated to a temperature of at least 50°C. In some embodiments, the separated calcium alpha-ketoglutarate is heated to a temperature of at least 60°C. In some embodiments, the separated calcium alpha-ketoglutarate is heated to a temperature of at least 70° C. In some embodiments, the separated calcium alpha-ketoglutarate is heated to a temperature of at least 80° C. In some embodiments, the separated calcium alpha-ketoglutarate is heated to a temperature of at least 90° C. In some embodiments, the separated calcium alpha-ketoglutarate is heated to a temperature of at least 100° C.

[0187] Drying time

[0188] In some embodiments, the separated calcium α-ketoglutarate is exposed to a heat source for 1 to 18 hours. In some embodiments, the separated calcium α-ketoglutarate is exposed to a heat source for 2 to 15 hours. In some embodiments, the separated calcium α-ketoglutarate is exposed to a heat source for 3 to 15 hours. In some embodiments, the separated calcium α-ketoglutarate is exposed to a heat source for 4 to 12 hours. In some embodiments, the separated calcium α-ketoglutarate is exposed to a heat source for 5 to 10 hours. In some embodiments, the separated calcium α-ketoglutarate is exposed to a heat source for 6 to 8 hours. In some embodiments, the separated calcium α-ketoglutarate is exposed to a heat source for 2 hours. In some embodiments, the separated calcium α-ketoglutarate is exposed to a heat source for 4 hours. In some embodiments, the separated calcium α-ketoglutarate is exposed to a heat source for 6 hours. In some embodiments, the separated calcium α-ketoglutarate is exposed to a heat source for 8 hours. In some embodiments, the isolated calcium alpha-ketoglutarate is exposed to the heat source for 10 hours. In some embodiments, the isolated calcium alpha-ketoglutarate is exposed to the heat source for 12 hours.

[0189] In another aspect, described herein is a method of preparing calcium alpha-ketoglutarate, the method comprising the steps of:

[0190] a) contacting alpha-ketoglutaric acid with a mixture of sodium bicarbonate and water to form disodium alpha-ketoglutarate; and

[0191] b) contacting the calcium salt and water mixture with disodium alpha-ketoglutarate to form calcium alpha-ketoglutarate;

[0192] wherein the sodium bicarbonate and water mixture contains 0.27 weight equivalents of sodium bicarbonate per weight equivalent of water;

[0193] wherein the α-ketoglutaric acid is 0.74 weight equivalent per weight equivalent of sodium bicarbonate;

[0194] wherein the α-ketoglutaric acid is contacted with the sodium bicarbonate aqueous solution at about 10°C to about 35°C, or at about 10°C to about 25°C;

[0195] wherein the solution of α-ketoglutaric acid and sodium bicarbonate water is stirred at about 10° C. to about 35° C., or at about 10° C. to about 25° C. for about 2 hours;

[0196] wherein the calcium salt is calcium chloride;

[0197] wherein the calcium salt and water mixture contains 0.2 to about 0.5 weight equivalents of the calcium salt per weight equivalent of water;

[0198] wherein the calcium salt is 0.95 weight equivalent per weight equivalent of α-ketoglutaric acid;

[0199] wherein the mixture of disodium α-ketoglutarate, the calcium salt and water is stirred at 65°C to 70°C; and

[0200] The mixture of α-ketoglutarate disodium, the calcium salt and water was stirred for 4 hours.

[0201] In another aspect, described herein is a method of preparing calcium alpha-ketoglutarate, the method comprising the steps of:

[0202] a) contacting alpha-ketoglutaric acid with a mixture of sodium carbonate and water to form disodium alpha-ketoglutarate; and

[0203] b) contacting the calcium salt and water mixture with disodium alpha-ketoglutarate to form calcium alpha-ketoglutarate;

[0204] wherein the sodium carbonate and water mixture contains 0.18 weight equivalent of sodium carbonate per weight equivalent of water;

[0205] wherein the α-ketoglutaric acid is 1.14 weight equivalents per weight equivalent of sodium carbonate;

[0206] wherein the α-ketoglutaric acid is contacted with the solution of sodium carbonate and water at about 10°C to about 35°C, or at about 10°C to about 25°C;

[0207] wherein the α-ketoglutaric acid and the solution of sodium carbonate and water are stirred at about 10°C to about 35°C, or at about 10°C to about 25°C for 2 hours;

[0208] wherein the calcium salt is calcium chloride;

[0209] wherein the calcium salt and water mixture contains from 0.2 to about 0.5 weight equivalents of the calcium salt per weight equivalent of water;

[0210] wherein the calcium salt is 0.95 weight equivalent per weight equivalent of α-ketoglutaric acid;

[0211] wherein the mixture of disodium α-ketoglutarate, the calcium salt and water is stirred at 65°C to 70°C; and

[0212] The mixture of α-ketoglutarate disodium, the calcium salt and water was stirred for 4 hours.

[0213] In some embodiments, the methods described herein reduce the formation of impurities formed during the method of preparing Ca-AKG using sodium hydroxide. In some embodiments, the impurities are calcium oxalate and calcium succinate. In some embodiments, the impurity is calcium oxalate. In some embodiments, the impurity is calcium succinate. In some embodiments, the impurity is an unidentified impurity. In some embodiments, the impurity is an unknown impurity.

[0214] In another aspect, described herein is a method of preparing dilithium alpha-ketoglutarate, the method comprising contacting an alpha-ketoglutaric acid and methanol mixture with lithium hydroxide to form dilithium alpha-ketoglutarate.

[0215] In some embodiments, the α-ketoglutaric acid and methanol mixture contains from 0.25 to 0.35 weight equivalents of α-ketoglutaric acid per weight equivalent of methanol. In some embodiments, the α-ketoglutaric acid and methanol mixture contains 0.32 weight equivalents of α-ketoglutaric acid per weight equivalent of methanol. In some embodiments, α-ketoglutaric acid is from 1.6 to 1.7 weight equivalents per weight equivalent of lithium hydroxide. In some embodiments, α-ketoglutaric acid is 1.66 weight equivalents per weight equivalent of lithium hydroxide. In some embodiments, the α-ketoglutaric acid and methanol mixture and lithium hydroxide are stirred for 2 to 3 hours. In some embodiments, the α-ketoglutaric acid and methanol mixture and lithium hydroxide are stirred at 50° C. to 55° C.

[0216] In another aspect, described herein is a method of preparing dipotassium alpha-ketoglutarate, the method comprising contacting an alpha-ketoglutaric acid and methanol mixture with potassium hydroxide to form dipotassium alpha-ketoglutarate.

[0217] In some embodiments, the α-ketoglutaric acid and methanol mixture contains from 0.25 to 0.35 weight equivalents of α-ketoglutaric acid per weight equivalent of methanol. In some embodiments, the α-ketoglutaric acid and methanol mixture contains 0.32 weight equivalents of α-ketoglutaric acid per weight equivalent of methanol. In some embodiments, α-ketoglutaric acid is from 1.3 to 1.4 weight equivalents per weight equivalent of potassium hydroxide. In some embodiments, α-ketoglutaric acid is 1.33 weight equivalents per weight equivalent of potassium hydroxide. In some embodiments, the α-ketoglutaric acid and methanol mixture and potassium hydroxide are stirred for 2 to 3 hours. In some embodiments, the α-ketoglutaric acid and methanol mixture and potassium hydroxide are stirred at 25° C. to 35° C.

[0218] In another aspect, described herein is a method of preparing zinc alpha-ketoglutarate, the method comprising the steps of:

[0219] a) contacting a mixture of α-ketoglutaric acid and water with a base, thereby forming disodium α-ketoglutarate; and

[0220] b) contacting disodium alpha-ketoglutarate with a mixture of a zinc salt and water to form zinc alpha-ketoglutarate.

[0221] In some embodiments, the base is sodium hydroxide. In some embodiments, the base is sodium bicarbonate. In some embodiments, the base is sodium carbonate.

[0222] In some embodiments, the alpha-ketoglutaric acid and water mixture contains 0.45 to 0.55 weight equivalents of alpha-ketoglutaric acid per weight equivalent of water. In some embodiments, the alpha-ketoglutaric acid and water mixture contains 0.5 weight equivalents of alpha-ketoglutaric acid per weight equivalent of water. In some embodiments, alpha-ketoglutaric acid is 1.6 to 1.7 weight equivalents per weight equivalent of sodium hydroxide. In some embodiments, alpha-ketoglutaric acid is 1.67 weight equivalents per weight equivalent of sodium hydroxide. In some embodiments, alpha-ketoglutaric acid is contacted with sodium hydroxide at 25°C to 35°C. In some embodiments, alpha-ketoglutaric acid and sodium hydroxide are stirred for 2 to 3 hours. In some embodiments, alpha-ketoglutaric acid and sodium hydroxide are stirred at 25°C to 35°C. In some embodiments, the zinc salt is zinc chloride. In some embodiments, the zinc salt and water mixture contains 0.25 to 0.35 weight equivalents of the zinc salt per weight equivalent of water. In some embodiments, the zinc salt and water mixture contains 0.3 weight equivalents of the zinc salt per weight equivalent of water. In some embodiments, the zinc salt is 1.2 weight equivalents per weight equivalent of alpha-ketoglutaric acid. In some embodiments, disodium alpha-ketoglutarate and the zinc salt and water mixture are stirred at 80° C. to 85° C. In some embodiments, disodium alpha-ketoglutarate and the zinc salt and water mixture are stirred for 4 to 5 hours.

[0223] Incorporated by Reference

[0224] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0225] Example

[0226] The following examples are provided for illustrative purposes only and are intended to merely illustrate the present disclosure and are not intended to limit the scope of the claims provided herein.

[0227] The conversion of α-ketoglutarate to a calcium salt has been reported previously. However, in the described method, as shown in Scheme 1, α-ketoglutarate is first converted to α-ketoglutarate disodium salt using sodium hydroxide.

[0228]

[0229]

[0230] It has been found herein that the preparation of Ca-AKG under those conditions results in the formation of impurities. The material in the process can be purified, but only to about 90.3 to 97.4% (see Examples 1 to 7). Furthermore, the conversion yields are only in the range of 55 to 83 weight / weight %.

[0231] It has been found that treating Ca-AKG or its hydrate with a 2% HCl solution can further reduce impurities and increase the purity to 99.22%. However, a simultaneous decrease in yield can also be seen.

[0232] It has been found herein that impurities are formed during the conversion of alpha-ketoglutarate to alpha-ketoglutarate disodium salt.For example, HPLC samples from the process of Example 7 showed that Ca-AKG was approximately 85% pure.

[0233] It was unexpectedly discovered herein that treatment of α-ketoglutarate with an alkali metal salt not only provides the di-salt of α-ketoglutarate, but more importantly greatly reduces the formation of impurities found in isolated Ca-AKG. See Example 8 and Scheme 2. When an alkali metal salt (such as sodium bicarbonate) was used, the HPLC samples in the process had a purity greater than 99%, indicating and showing negligible impurity formation. Once isolated and dried, Ca-AKG (Example 11) had a purity of 99.3% and the single largest unknown impurity (SUI) was measured to be only 0.46%.

[0234]

[0235] Importantly, the process was found to be fully scalable and was illustratively replicated on a 50 kg batch (Example 9). The analytical results of Examples 8 and 9 were similar, indicating that scaling up the reaction did not result in an increase in impurities.

[0236] In addition, it was unexpectedly found that the yield obtained with the 50 kg batch was actually increased (from 81.2 to 94.2%) compared to the 500 g batch. The methods and processes described herein result in improved separation without the need for additional purification, resulting in a reduction in plant unit operations, thus avoiding product losses (yield reduction) and additional costs.

[0237] Similar results are seen for alternative alkali metal salts such as sodium carbonate. It was found that treatment of alpha-ketoglutarate with sodium carbonate also greatly reduced the formation of impurities found in isolated Ca-AKG (see Example 10). See Scheme 3.

[0238]

[0239] Example 1. Synthesis of Ca-AKG using NaOH (250 g scale). Sodium hydroxide (150 g, 3.76 mol) was dissolved in 1000 mL of water. Alpha-ketoglutaric acid (250.0 g, 1.71 mol) was added at 25 to 35 ° C. The solution was stirred for 2 to 3 hours at 25 to 35 ° C. Calcium chloride (569 g, 5.13 mol, 3.0 equivalents) dissolved in 1000 mL of water was added to the reaction mass at 25 to 35 ° C. The reaction mass was stirred for 4 to 5 hours at 65 to 70 ° C. The resulting precipitate was collected and washed with 500 mL of water. The solid was dried for 6 hours at 80 to 90 ° C to produce 265 g (77% yield).

[0240] Example 2. Synthesis of Ca-AKG using NaOH (50 g scale). Sodium hydroxide (30 g, 0.75 mol, 2.2 eq) was dissolved in 200 mL of water. Alpha-ketoglutaric acid (50.0 g, 0.342 mol) was added at 25 to 35 ° C. The solution was stirred for 2 to 3 hours at 25 to 35 ° C. Calcium chloride (113 g, 1.026 mol, 3.0 eq) dissolved in 200 mL of water was added to the reaction mass at 60 to 70 ° C. The reaction mass was stirred for 4 to 5 hours at 60 to 70 ° C. The resulting precipitate was collected and washed with 100 mL of water. The solid was dried for 6 to 8 hours at 70 to 80 ° C to produce 53.8 g (78% yield).

[0241] Example 3. Synthesis of Ca-AKG using NaOH (50 g scale) and reverse addition of CaCl2 (1 eq.). Sodium hydroxide (30 g, 0.75 mol, 2.2 eq.) was dissolved in 200 mL of water. Alpha-ketoglutaric acid (50.0 g, 0.342 mol) was added at 25 to 35 °C. The solution was stirred for 2 to 3 hours at 25 to 35 °C. The reaction mass was added to a solution of calcium chloride (38 g, 0.342 mol, 1.0 eq.) dissolved in 200 mL of water at 25 to 35 °C. The reaction mass was stirred for 4 to 5 hours at 65 to 70 °C. The resulting precipitate was collected and washed with 100 mL of water. The solid was dried at 70 to 80 °C for 6 to 8 hours to produce 37.9 g (55% yield).

[0242] Example 4. Synthesis of Ca-AKG using NaOH (50 g scale) and reverse addition of CaCl2 (2 eq.). Sodium hydroxide (30 g, 0.75 mol, 2.2 eq.) was dissolved in 200 mL of water. Alpha-ketoglutaric acid (50.0 g, 0.342 mol) was added at 25 to 35 °C. The solution was stirred for 2 to 3 hours at 25 to 35 °C. The reaction mass was added to a solution of calcium chloride (76 g, 0.684 mmol, 2.0 eq.) dissolved in 200 mL of water at 25 to 35 °C. The reaction mass was stirred for 4 to 5 hours at 65 to 70 °C. The resulting precipitate was collected and washed with 100 mL of water. The solid was dried at 70 to 80 °C for 6 to 8 hours to produce 55.89 g (81% yield).

[0243] Example 5. Synthesis of Ca-AKG using NaOH (100 g scale) and reverse addition of CaCl2 (1.3 eq.). Sodium hydroxide (60 g, 1.5 mol, 2.2 eq.) was dissolved in 200 mL of water. Alpha-ketoglutaric acid (100.0 g, 0.684 mol) was added at 25 to 35 °C. The solution was stirred for 2 to 3 hours at 25 to 35 °C. The reaction mass was added to a solution of calcium chloride (100 g, 0.903 mol, 1.32 eq.) dissolved in 200 mL of water at 25 to 35 °C. The reaction mass was stirred for 4 to 5 hours at 65 to 70 °C. The resulting precipitate was collected and washed with 100 mL of water. The solid was dried at 70 to 80 °C for 6 to 8 hours to produce 103.5 g (75% yield).

[0244] Example 6. Synthesis of Ca-AKG using NaOH (500 g scale) and reverse addition of CaCl2 (1.3 eq.). Sodium hydroxide (300 g, 7.53 mol) was dissolved in 1000 mL of water. Alpha-ketoglutaric acid (500.0 g, 3.4 mmol) was added at 15 to 20 °C. The solution was stirred for 2 to 3 hours at 15 to 20 °C. The reaction mass was added to a solution of calcium chloride (500 g, 4.5 mol, 1.32 eq.) dissolved in 1000 mL of water at room temperature. The reaction mass was stirred for 4 to 5 hours at 80 to 85 °C. The resulting precipitate was collected and washed with 500 mL of water. The solid was dried at 80 to 85 °C for 6 to 8 hours to produce 579.5 g (84% yield).

[0245] Example 7. Synthesis of Ca-AKG using NaOH (100 g scale) and HCl wash. Sodium hydroxide (60 g, 1.50 mol) was dissolved in 200 mL of water. Alpha-ketoglutaric acid (100.0 g, 0.684 mol) was added at 15 to 20 °C. The solution was stirred for 2 to 3 hours at 15 to 20 °C. The reaction mass was added to a solution of calcium chloride (100 g, 0.903 mol, 1.32 equiv) dissolved in 200 mL of water at room temperature. The reaction mass was stirred for 4 to 5 hours at 80 to 85 °C. The resulting precipitate was collected and washed with 100 mL of water. The wet slurry was added to 2% HCl solution (200 mL) and the reaction mass was stirred for 1 to 2 hours at 80 to 85 °C. The resulting precipitate was collected and washed with 100 mL of water. The solid was dried for 6 to 8 hours at 80 to 85 °C to produce 103.5 g (75% yield).

[0246] Example 8. Synthesis of Ca-AKG using NaHCO3 (500g scale). Sodium bicarbonate (690g, 8.21mol) was suspended in 3000mL water. Alpha-ketoglutaric acid (500.0g, 3.4mol) was added at 15 to 20°C. The solution was stirred for 2 hours at 15 to 20°C. The reaction mass was added to a solution of calcium chloride (500g, 4.5mol, 1.32 equivalents) dissolved in 1000mL water at room temperature. The reaction mass was stirred for 4 to 5 hours at 65 to 70°C. The resulting precipitate was collected and washed with 500mL water. The solid was dried for 6 to 8 hours at 80 to 85°C to produce 558.9g (81% yield).

[0247] Example 9. Synthesis of Ca-AKG using NaHCO3 (50 kg scale). α-Ketoglutaric acid (50 kg) was added to 250 L of water at 25 to 35 ° C. Sodium bicarbonate (69 kg) was slowly added to the reaction mass at 25 to 35 ° C. The reaction mass was stirred until the reaction pH was (7.4 ± 0.4). The reaction mass was added to a solution of calcium chloride (50 kg) in 125 L of water at 25 to 35 ° C. The reaction mass was heated at 65 to 70 ° C for 4 hours and then cooled to 45 to 50 ° C. The precipitate was collected by filtration and the resulting filter cake was washed with 50 L of water. The filter cake was combined with 150 L of water and the reaction mass was heated at 65 to 70 ° C for 1 hour, then cooled to 45 to 50 ° C. The solid was collected by filtration and the filter cake was washed with 50 L of water. The filter cake was dried under vacuum at 50 to 60° C. until the moisture content was 8.5 to 10.0% to provide 65 kg of calcium α-ketoglutarate.

[0248] Example 10. Synthesis of Ca-AKG using Na2CO3 (25 g scale). Sodium carbonate (22.0 g, 0.205 mol) was suspended in 125 mL of water. Alpha-ketoglutaric acid (25.0 g, 0.171 mol) was added at 25 to 30 °C. The solution was stirred for 2 hours at 25 to 35 °C. The reaction mass was added to a solution of calcium chloride (23.7 g, 0.213 mol) dissolved in 100 mL of water at room temperature. The reaction mass was stirred for 4 to 5 hours at 65 to 70 °C. The resulting precipitate was collected and washed with 25 mL of water. The wet slurry was added to 100 mL of water and the reaction mass was stirred for 1 to 2 hours at 65 to 70 °C. The resulting precipitate was collected and washed with 25 mL of water. The wet slurry was added to 2% HCl solution (100 mL) and the reaction mass was stirred for 1 to 2 hours at 65 to 70 °C. The resulting precipitate was collected and washed with 25 mL of water. The solid was added to 100 mL of water and the reaction mass was stirred at 65 to 70°C for 1 to 2 hours. The resulting precipitate was collected and washed with 25 mL of water. The solid was dried at 50 to 60°C for 5 to 6 hours to yield 28.0 g (yield = 81.1%).

[0249] Example 11. Synthesis of Ca-AKG using NaHCO3 (500 kg scale). Alpha-ketoglutaric acid (499.8 kg, 3421 mol) was dissolved in 2500 L of water at 25 to 35 °C. Sodium bicarbonate (675 kg, 8035 mol) was added to the reaction mass at 25 to 35 °C for 2 to 4 hours. The solution was stirred for 2 hours at 25 to 35 °C. The reaction mass was added to a solution of calcium chloride (475 kg, 4280 mol) dissolved in 1500 mL of water at 25 to 35 °C. The reaction mass was stirred for 4 hours at 65 to 70 °C. The reaction mass was cooled to 45 to 55 °C and the precipitate was collected in a stirred Nutsche filter dryer. The precipitate was stirred in 2500 L of water at 45 to 55 °C for 2 hours and then filtered. The solid was washed with 1000 L of water. The solid was dried at 50 to 60° C. to provide 651.78 kg of calcium α-ketoglutarate monohydrate.

[0250] Example 12. Comparison of impurity data. A comparison of impurity data for Examples 7, 8, 10 and 11 is given in Table 1 below.

[0251] Table 1.

[0252]

[0253]

[0254] a. List only those higher than > 0.05% impurities

[0255] Related compounds identified by HPLC:

[0256] Preparation of buffer: Weigh and transfer about 2.72 g of potassium dihydrogen phosphate into 1000 mL of water and dissolve and mix. Add 2.0 mL of orthophosphoric acid to the buffer solution and mix. Filter through a 0.45u or finer pore membrane filter.

[0257] Mobile phase A: Buffer and methanol (95:05) v / v was used.

[0258] Mobile phase B: Buffer and methanol (50:50) v / v was used.

[0259] Preparation of dilute hydrochloric acid: Transfer 0.8 mL of hydrochloric acid to a 100 mL volumetric flask containing approximately 50 mL of cold water, dilute to volume with water and mix.

[0260] Preparation of blank solution: Accurately transfer 5 mL of dilute HCl into a 20 mL volumetric flask and fill to the mark with diluent.

[0261] Preparation of Ca-succinic acid stock solution: accurately weigh about 5.0 mg of Ca-succinic acid and transfer to a 25 mL volumetric flask, add 10 mL of water and sonicate and mix, add 5 mL of dilute HCl and sonicate until dissolved. Make up the volume to the mark with diluent and mix.

[0262] Preparation of Ca-oxalic acid stock solution: accurately weigh about 5.0 mg of Ca-oxalic acid and transfer to a 25 mL volumetric flask, add 10 mL of water and sonicate and mix, add 5 mL of dilute HCl and sonicate until dissolved. Make up the volume to the mark with diluent and mix.

[0263] Preparation of COF stock solution: accurately weigh about 5.0 mg COF and transfer to a 25 mL volumetric flask, add 10 mL water and sonicate and mix, add 5 mL dilute HCl and sonicate until dissolved. Make up the volume to the mark with diluent and mix.

[0264] Preparation of system suitability solutions: Accurately transfer 5 mL each of Ca-succinic acid, Ca-oxalic acid and COF stock solutions into a 20 mL volumetric flask and make up with diluent and mix.

[0265] Preparation of standard solutions: 2.5 mL of each Ca-succinic acid, Ca-oxalic acid and COF stock solution was accurately transferred into a 20 mL volumetric flask and made up with diluent and mixed.

[0266] Preparation of sample solution: accurately weigh about 100.0 mg of the test sample and transfer it to a 20 mL volumetric flask, add 10 mL of water and sonicate and mix, add 5 mL of dilute HCl and sonicate until dissolved. Make up the volume to the mark with diluent and mix.

[0267] Procedure: Inject a blank solution (in duplicate) into the chromatograph and record the chromatogram. Ignore the average blank peak area from known impurities (if present).

[0268] The injection sequence is as follows:

[0269] Injection order Number of injections blank 2 System Suitability Solutions 6 Standard solution 2 Sample solution 1 Standard (calibration test) 1

[0270] Assessment of system suitability: Inject the system suitability solution six times into the chromatograph and record the chromatogram.

[0271] Inject the standard solution (in duplicate), sample solution into the chromatograph and record the chromatogram. Ignore the blank peak from the sample chromatogram and calculate the result.

[0272] Calculation: Calculate the average area and concentration of COF standards for unknown and total impurities

[0273]

[0274] Ru = peak response of each impurity peak from sample solution (known / individual unknown / total except COF peak).

[0275] Rs = average area peak response of the corresponding standard from the standard solution.

[0276] Cu = concentration of sample solution.

[0277] Cs = concentration of the corresponding standard substance in the standard solution.

[0278] P = potency corresponding to the standard

[0279] Analysis by HPLC: (hence wt / wt %)

[0280] Buffer and dilute hydrochloric acid were prepared as above.

[0281] Mobile phase: Buffer and methanol (95:05) v / v was used.

[0282] Preparation of blank solution: Take 1 mL of diluted HCl in a 10 mL volumetric flask and make up to the mark with diluent and mix.

[0283] Preparation of standard solution: accurately weigh about 100.0 mg of the standard and transfer to a 100 mL volumetric flask, add 30 mL of diluent and sonicate and mix, add 10 mL of dilute HCl and sonicate until dissolved. Make up the volume to the mark with diluent and mix.

[0284] Preparation of sample solution: accurately weigh about 100.0 mg of the test sample and transfer it to a 100 mL volumetric flask, add 30 mL of diluent and sonicate and mix, add 10 mL of dilute HCl and sonicate until dissolved. Make up the volume to the mark with diluent and mix.

[0285] Evaluation of Blank: Inject the blank solution into the chromatograph and record the chromatogram. No peak should be observed at the retention time of the analyte.

[0286] Evaluation of system suitability: Inject the standard solution into the chromatograph five times and record the chromatogram.

[0287] Procedure: Repeated injection of sample solution into the chromatograph and recording of chromatograms.

[0288] The injection sequence is as follows:

[0289] order Number of injections blank 1 Standard solution 5 Sample solution 2 Standard calibration test 1

[0290]

[0291] AT = average area of ​​COF peak in sample solution

[0292] AS = average area of ​​COF peaks in standard solution

[0293] CS = concentration of standard solution

[0294] CT = concentration of sample solution

[0295] P = potency of COF standard

[0296] Calcium α-ketoglutarate monohydrate reference standard was prepared as described in Example 12. The analytical results are presented in Table 2, Table 3, Table 4 and Table 5.

[0297] Example 13. Synthesis of α-ketoglutarate calcium monohydrate reference standard

[0298] Sodium bicarbonate (552g, 6.57mol) is dissolved in 2000mL water. α-Ketoglutaric acid (400g, 2.73mol) is added at 15 to 20°C. The solution is stirred for 2 hours at 15 to 20°C. The reaction mass is added to a solution of calcium chloride (400g, 3.61mol) dissolved in 800mL water at room temperature. The reaction mass is stirred for 4 to 5 hours at 65 to 70°C. The resulting precipitate is collected and washed with 400mL water. The wet slurry is added to 1200mL water and heated at 65 to 70°C for 1 hour. The reaction mixture is cooled to 40 to 45°C. The reaction mixture is filtered and washed with 400mL water. At 50 to 60°C, the solid is dried for 10 hours to produce 501g (yield: 1.25w / w).

[0299] Table 2. Calcium α-ketoglutarate monohydrate reference standard

[0300]

[0301]

[0302] Table 3. Alpha-ketoglutarate calcium monohydrate reference standard 1 H-NMR data

[0303] Serial number Chemical shift (ppm) Relative integral Multiplicity Coupling constant Assignment 1 2.515 2H t 6.4Hz <![CDATA[C(7)H2]]> 2 3085 2H t 6.8hz <![CDATA[C(6)H2]]>

[0304] Table 4. Alpha-ketoglutarate calcium monohydrate reference standard 13 C-NMR data

[0305] Serial number Chemical shift (ppm) Carbon Type Assignment 1 30.73 <![CDATA[CH2]]> C(6) 2. 35.61 CH2 C(7) 3 169.53 C=O C(4),C(8) 4 181.73 C=O C(5)

[0306] Table 5. FT-IR data of calcium α-ketoglutarate monohydrate reference standard

[0307] <![CDATA[Absorption band (cm -1 )]]> Assignment 3501.4 OH 1703.9 C=O 1651.3 C=O 1562.8 C=O

[0308] Example 15. Synthesis of dilithium salt of AKG (Li2-AKG). Alpha-ketoglutaric acid (10.0 g, 0.068 mol) was dissolved in 40 mL of methanol. Lithium hydroxide (6.0 g, 0.142 mol) was added to the solution. The solution was stirred at 50 to 55 ° C for 2.0 to 3.0 hours. The resulting precipitate was separated and the filter cake was washed with 10 mL of methanol. The solid was dried at 75 to 80 ° C for 5 to 6 hours to produce 7.56 g (70% yield).

[0309] Example 16. Synthesis of the dipotassium salt of AKG (K2-AKG). Alpha-ketoglutaric acid (10.0 g, 0.068 mol) was dissolved in 40 mL of methanol and stirred at ambient temperature to a clear solution. Potassium hydroxide (7.54 g, 0.134 mol) was added to the solution. The solution was stirred at 25 to 35 °C for 2.0 to 3.0 hours. The resulting precipitate was separated and the filter cake was washed with 10 mL of methanol. The solid was dried at 75 to 85 °C for 5 to 6 hours to produce 7.8 g (52% yield).

[0310] Example 17. Synthesis of zinc salt of AKG (Zn-AKG): α-ketoglutaric acid (10.0 g, 0.068 mol) was dissolved in 20 mL of water. Sodium hydroxide (6.0 g, 0.149 mol) was added to the α-ketoglutaric acid solution. The solution was stirred for 2.5 to 3.0 hours at 25 to 35° C. Zinc chloride solution (12.0 g, 0.088 mol, 1.32 equivalents dissolved in 40 mL of water) was added to the reaction mass. After complete addition of the zinc chloride solution, the reaction mass was stirred for 4 to 5 hours at 80 to 85° C. The resulting precipitate was collected and washed with 10 mL of water. The solid was dried at 80 to 85° C. for 6 to 8 hours to produce 10.2 g (73% yield).

[0311] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Those skilled in the art will now appreciate that many variations, changes, and substitutions may be made without departing from the present invention. It should be understood that various alternatives to the embodiments of the disclosure described herein may be used to practice the present invention. The following claims are intended to define the scope of the present invention and thereby cover methods and structures within the scope of these claims and their equivalents.

Claims

1. A method for preparing calcium α-ketoglutarate, the method comprising: a) contacting α-ketoglutaric acid with an alkali metal salt of an acid selected from the group consisting of lithium, sodium and potassium bicarbonates, lithium, sodium and potassium carbonates, and combinations thereof, thereby forming a double salt of α-ketoglutaric acid; and b) contacting the double salt of α-ketoglutarate with a calcium salt, thereby forming calcium α-ketoglutarate.

2. A method for preparing calcium α-ketoglutarate, the method comprising: a) contacting α-ketoglutaric acid with an alkali metal salt of an acid and water to form a solution having a pH in the range of from 5.0 to 11.9, thereby forming a double salt of α-ketoglutaric acid, wherein the alkali metal salt of the acid is selected from the group consisting of lithium, sodium and potassium bicarbonates, lithium, sodium and potassium carbonates, and combinations thereof; and b) contacting the double salt of α-ketoglutarate with a calcium salt and water to form calcium α-ketoglutarate.

3. The method of claim 1, wherein the alpha-ketoglutaric acid is mixed with water.

4. The method according to claim 3, wherein the α-ketoglutarate and water mixture is prepared from or contains from 0.05 to 0.5 weight equivalent of α-ketoglutarate per weight equivalent of water.

5. The method of claim 1, wherein the alkali metal salt is mixed with water.

6. The process according to claim 5, wherein the alkali metal salt and water mixture is prepared from or contains from 0.1 to 0.35 weight equivalents of alkali metal salt per weight equivalent of water.

7. The method of any one of claims 1 to 6, wherein the alkali metal salt is selected from the group consisting of sodium and potassium bicarbonates, sodium and potassium carbonates, and combinations thereof.

8. The method according to any one of claims 1 to 6, wherein the alkali metal salt is sodium bicarbonate, sodium carbonate, or a mixture thereof.

9. The process according to any one of claims 1 to 6, wherein the alkali metal salt is sodium bicarbonate.

10. The process of claim 9, wherein the sodium bicarbonate and water mixture contains from 0.2 to 0.3 weight equivalents of sodium bicarbonate per weight equivalent of water.

11. The process according to any one of claims 1 to 6, wherein the alkali metal salt is sodium carbonate.

12. The process of claim 11, wherein the sodium carbonate and water mixture contains from 0.05 to 0.2 weight equivalents of sodium carbonate per weight equivalent of water.

13. The method according to any one of claims 1 to 6, wherein the alkali metal salt is added to the alpha-ketoglutaric acid to form a mixture having a pH of at least 6.5, optionally after a predetermined period of time.

14. The method according to any one of claims 1 to 6, wherein the alkali metal salt is added to the alpha-ketoglutaric acid to form a mixture having a pH from 6.5 to 9, optionally after a predetermined period of time.

15. The method according to any one of claims 1 to 6, wherein the α-ketoglutaric acid is from 0.5 to 3 weight equivalents per weight equivalent of the alkali metal salt.

16. The method of claim 9, wherein the alpha-ketoglutarate is from 0.7 to 0.9 weight equivalent per weight equivalent of sodium bicarbonate.

17. The method of claim 11, wherein the alpha-ketoglutaric acid is from 1.0 to 2.8 weight equivalents per weight equivalent of sodium carbonate.

18. The method of claim 9, wherein the alpha-ketoglutaric acid is contacted with the sodium bicarbonate and water mixture at 50°C or below.

19. The method of claim 9, wherein the α-ketoglutaric acid is contacted with the sodium bicarbonate and water mixture at 10°C to 50°C.

20. The method of claim 9, wherein the alpha-ketoglutaric acid is contacted with the sodium bicarbonate and water mixture at 10°C to 35°C.

21. The method of claim 9, wherein the alpha-ketoglutaric acid and the sodium bicarbonate and water mixture are stirred for at least 30 minutes.

22. The method of claim 9, wherein the alpha-ketoglutaric acid and the sodium bicarbonate and water mixture are stirred for at least 1 hour.

23. The method of claim 9, wherein the alpha-ketoglutaric acid and the sodium bicarbonate and water mixture are stirred for at least 2 hours.

24. The method of any one of claims 1 to 6, wherein the calcium salt is selected from the group consisting of calcium formate, calcium acetate, and calcium chloride.

25. The method of claim 24, wherein the calcium salt is calcium chloride.

26. The method of any one of claims 1 to 6, wherein the calcium salt is mixed with water.

27. The method of claim 26, wherein the calcium salt and water mixture is prepared from or contains from 0.1 to 1 weight equivalent of the calcium salt per weight equivalent of water.

28. The method according to any one of claims 1 to 6, wherein the calcium salt is from 0.5 to 2 weight equivalents per weight equivalent of alpha-ketoglutaric acid.

29. The method of claim 26, wherein the double alkali metal salt of alpha-ketoglutarate is contacted with the calcium salt and water mixture at 40°C to 90°C.

30. The method of claim 26, wherein the double alkali metal salt of alpha-ketoglutarate and the calcium salt and water mixture are stirred for at least 30 minutes.

31. The method of any one of claims 1 to 6, further comprising drying the calcium alpha-ketoglutarate.

32. The method of any one of claims 1 to 6, further comprising drying the calcium alpha-ketoglutarate to a moisture content of 20% to 5%.

33. The method of any one of claims 1 to 6, further comprising drying the calcium alpha-ketoglutarate, wherein the dried calcium alpha-ketoglutarate is less than 50% calcium alpha-ketoglutarate dihydrate.

34. The method of any one of claims 1 to 6, further comprising drying the calcium alpha-ketoglutarate, wherein the dried calcium alpha-ketoglutarate is at least 50% calcium alpha-ketoglutarate monohydrate.

35. A method for preparing calcium α-ketoglutarate, the method comprising: a) contacting α-ketoglutaric acid with a solution of sodium bicarbonate and water to form disodium α-ketoglutarate; and b) contacting the disodium α-ketoglutarate with a solution of calcium chloride and water to form calcium α-ketoglutarate; wherein the solution of sodium bicarbonate is prepared from 0.27 weight equivalent of sodium bicarbonate per weight equivalent of water; wherein the α-ketoglutaric acid is 0.74 weight equivalent per weight equivalent of sodium bicarbonate; wherein the α-ketoglutaric acid is contacted with the solution of sodium bicarbonate and water at 10°C to 35°C; wherein the α-ketoglutaric acid, the sodium bicarbonate and the water solution are stirred at 10° C. to 35° C. for 2 hours; wherein the solution of calcium chloride is prepared from 0.2 to 0.5 weight equivalent of calcium chloride per weight equivalent of water; wherein the calcium chloride is 0.95 weight equivalent per weight equivalent of α-ketoglutaric acid; The disodium α-ketoglutarate and the calcium chloride solution are stirred at 65° C. to 70° C. for 4 hours.

36. A method for preparing calcium α-ketoglutarate, the method comprising: a) contacting α-ketoglutaric acid with a solution of sodium carbonate and water to form disodium α-ketoglutarate; and b) contacting the disodium α-ketoglutarate with a solution of calcium chloride and water to form calcium α-ketoglutarate; wherein the solution of sodium carbonate is prepared from 0.18 weight equivalent of sodium carbonate per weight equivalent of water; wherein the α-ketoglutaric acid is 1.14 weight equivalents per weight equivalent of sodium carbonate; wherein the α-ketoglutaric acid is contacted with the solution of sodium carbonate and water at 10°C to 35°C; wherein the α-ketoglutaric acid, the sodium carbonate and the water solution are stirred at 10° C. to 35° C. for 2 hours; wherein the solution of calcium chloride is prepared from 0.2 to 0.5 weight equivalent of calcium chloride per weight equivalent of water; wherein the calcium chloride is 0.95 weight equivalent per weight equivalent of α-ketoglutaric acid; The solution of the disodium α-ketoglutarate, the calcium chloride and water is stirred at 65° C. to 70° C. for 4 hours.

37. The method of claim 35 or 36, wherein the alpha-ketoglutaric acid is contacted with the solution of sodium bicarbonate and water at 10°C to 25°C.

38. The process of claim 35 or 36, wherein the solution of alpha-ketoglutaric acid and sodium carbonate and water is stirred at 10°C to 25°C for 2 hours.

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