Patent Application
20250051274
Embodiments of the present invention are generally related to 2-hydroxy-5-oxoproline. More particularly, embodiments are related to methods for preparing 2-hydroxy-5-oxoproline salt. Embodiments are also related to the preparation of 2-hydroxy-5-oxoproline salt by dissolving Sodium 2-pyrrolidone-5-carboxylate in aqueous solution and reacting a molar excess of ozone with the aqueous solution of sodium 2-pyrrolidone-5-carboxylate at a temperature between 20° C. and 100° C. such that sodium 2-hydroxy-5-oxoproline is formed.
The metabolite 2-hydroxy-5-oxoproline (2-oxoglutaramate) was discovered several decades ago in animal livers and kidneys and investigated in these tissues. A limited understanding of its function in animals was developed from these studies, in cells this material appears to be made by the physiologically irreversible transamination of glutamine. The compound appears to play a role in the regulation of tissue glutamine levels and in ammonia genesis, that is, the amide nitrogen in glutamine is a major Source of urinary ammonia. See, e.g., “The Glutamine Transaminase-co-Amidase Pathway” by Arthur J. L. Cooper and Alton Meister, CRC Critical Reviews in Biochemistry, pages 281-303, January 1977, and “Occurrence Of Glutamine-2-Oxoacid Transaminase Activity In The Blue Green Alga ANABAENACYLINDRICA” by Masayuki Ohmori et al., J. Gen Appl. Microbiol. 31, 171 (1985).
More recently, 2-hydroxy-5-oxoproline has been found to have significant effect on plant growth. See, e.g., “Use Of Prolines For Improving Growth And Other Properties Of Plants And Algae’ by Pat J. Unkefer, Thomas J. Knight, and Rodolfo A. Martinez, U.S. Patent and Trademark Office Ser. No. 09/493,039, filed on Jan. 27, 2000, where the inventors describe the use of the chemical class of compounds known as prolines for improving plant properties and performance.
In the past, 2-hydroxy-5-oxoproline has been synthesized using enzymatic procedures which are slow and difficult to control. See, e.g., A. L. Cooper and Alton Meister, Supra.
The reaction of Fremy's Salt with glutamic acid to yield (21%) an a-ketoacid of glutamic acid is described in “Oxidation of a-Amino Acids and a-Hydroxy Acids By Fremy's Salt. A Model For Oxidases?” by Angel Garcia-Raso, J. Org. Chem. 51, 4285 (1986). More particularly, L-glutamic acid was used as the starting material.
The quantitative chemical synthesis for this 2-hydroxy-5-oxoproline has been performed in a single step reaction of Fremy's Salt with either glutamine or 2-pyrrolidone-5-carboxylic acid, as was described by one of the present inventors (Martinez) in U.S. Pat. No. 6,288,240, entitled “preparation of 2-hydroxy-5-oxoproline and analogs thereof”, which was granted Sep. 11, 2001. A product was produced in near quantitative yield. However, this process produced a waste stream that prevented its use for the commercial production of 2-hydroxy-5-oxoproline.
What is needed is a process that does not produce any waste and can be used as the commercial product when produced.
The following summary is provided to facilitate an understanding of some of the features of the disclosed embodiments and is not intended to be a full description. A full appreciation of the various aspects of the embodiments disclosed herein can be gained by taking the specification, claims, drawings, and abstract as a whole.
In accordance with a feature of the embodiments, a method is provided for preparing 2-hydroxy-5-oxoproline salt that includes the steps of: dissolving Sodium 2-pyrrolidone-5-carboxylate in aqueous solution and reacting a molar excess of ozone with the aqueous solution of sodium 2-pyrrolidone-5-carboxylate at a temperature between 20° C. and 50° C. such that sodium 2-hydroxy-5-oxoproline salt is formed.
In accordance with another feature of the embodiments, an aqueous solution of hydrogen peroxide can be reacted with the said solution of sodium 2-pyrrolidone-5-carboxylate at a temperature between 20° C. and 100° C.
In accordance with yet another feature of the embodiments, a method for preparing 2-hydroxy-5-oxoproline can further include the step of adjusting the pH of an aqueous solution of 2-pyrrolidone-5-carboxylic acid to pH7 with alkali metal hydroxides (i.e., sodium hydroxide, potassium hydroxide, calcium hydroxide, etc.).
In accordance with another feature of the embodiments, a method for preparing 2-hydroxy-5-oxoproline can further include the steps of adjusting the pH of an aqueous solution of 2-pyrrolidone-5-carboxylic acid to pH7 with alkali metal carbonates or bicarbonates (i.e., sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.).
These and other aspects of the embodiments will become more apparent in light of the detailed specification and drawings that follow.
The accompanying figures, in which like reference numerals refer to identical or functionally similar elements throughout the separate views and which are incorporated in and form a part of the specification, further illustrate the present invention and, together with the detailed description of the invention, serve to explain the principles of the present invention.
The particular values and configurations discussed in these non-limiting examples can be varied and are cited merely to illustrate one or more embodiments and are not intended to limit the scope thereof.
Subject matter will now be described more fully hereinafter with reference to the accompanying drawings, which form a part hereof, and which show, by way of illustration, specific example embodiments. Subject matter may, however, be embodied in a variety of different forms and, therefore, covered or claimed subject matter is intended to be construed as not being limited to any example embodiments set forth herein; example embodiments are provided merely to be illustrative. Likewise, a reasonably broad scope for claimed or covered subject matter is intended. Among other issues, subject matter may be embodied as methods, devices, components, or systems. Accordingly, embodiments may, for example, take the form of hardware, software, firmware, or a combination thereof. The following detailed description is, therefore, not intended to be interpreted in a limiting sense.
In accordance with a feature of the embodiments, a method is disclosed for preparing 2-hydroxy-5-oxoproline. Referring to
Referring to
EXAMPLE: sodium L-glutamic acid or sodium L-pyroglutamic acid was reacted with an oxidant such as hydrogen peroxide or ozone. The reaction is allowed to proceed until the 4-hydroxypyroglutamic acid, sodium salt is formed. A typical reaction can be done as follows. Sodium pyroglutamate (20.4 g, 0.13 moles) was dissolved in water (100 mL). The homogenous colorless solution (pH=7) can be placed in an ambient temperature water bath to dissipate any heat produced in the reaction. The desired product can be synthesized using several radical reagents such as hydrogen peroxide (H2O2) and Ozone. The NMR and HPLC data are as follow:
NMR Data:
4-hydroxypyroglutamic acid, sodium salt
13C NMR (H2O (unlocked), 75 MHz): δ=29, 34, 89, 177, 181
HPLC (ICSep ICE-ION-300 Column) (1% H2SO4, 0.4 mL/min) r.t.=20.817 min
In this example ozone was bubbled through the solution at 2 L/min for a total of 21 hours monitoring the disappearance of the SM (chemical shift=61 ppm) and subsequent appearance of the desired product (chemical shift=89 ppm). After this period nitrogen gas can be passed bubbled in the solution to remove excess ozone. An NMR analysis shows the expected 4-hydroxypyroglutamic acid, sodium salt and small amounts of by-products, succinimide and succinic acid sodium salt.
Another example of a typical scaled reaction is as follows: Sodium pyroglutamate (20.4 g, 0.13 moles) was dissolved in water (100 mL). The homogenous colorless solution (pH=7) was placed in an ambient temperature water bath to dissipate any heat produced in the reaction. The desired product has been synthesized using several radical reagents such as hydrogen peroxide (H2O2) and Ozone. In this example ozone was bubbled through the solution at 2 L/min for a total of 21 hours monitoring the disappearance of the SM (chemical shift=61 ppm) and subsequent appearance of the desired product (chemical shift=89 ppm). After this period nitrogen gas is passed bubbled in the solution to remove excess ozone. An NMR analysis shows that the expected 4-hydroxypyroglutamic acid, sodium salt and small amounts of by-products, succinimide and succinamic acid sodium salt.
It can be appreciated that the reaction can be scaled to multikilogram quantities by using a larger ozone generator and larger reactors.
A typical scaled reaction produced 140 Kg of product in 12-13 days of reaction time. The reaction rate can be increased or decreased by regulating the amount of ozone that is introduced to the reaction. Once the reaction is complete, compressed air is bubbled into the reaction to remove excess ozone. The product is used as produced without further purification.
It will be appreciated that variations of the above-disclosed embodiments and examples and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. It will also be appreciated that various presently unforeseen or unanticipated alternatives, modifications, variations, or improvements therein may be subsequently made by those skilled in the art which are also intended to be encompassed by the following claims.
