Inventor: Thomas Daly

BACKGROUND

Field of the Invention

The present invention relates generally to the field of amines and more particularly to a classes of amines used as buffers in biological systems.

Description of the Problem Solved by the Invention

Amines are very useful compounds in the buffering of biological systems. Each class of amine has various limitations which require choosing an amine based on multiple factors to select the best amine. For example, pH buffering range is typically most important, but issues of chelation, and pH range stability, and solubility also come into play. Typically, a suboptimal buffer will result in yields that are well below the potential yield. The invention disclosed improves the yields in

fermentation and purification, and improves shelf stability of proteins and amino acids.

SUMMARY OF THE INVENTION

The present invention relates to amines and amine derivatives that improve the buffering range, and / or reduce the chelation and other negative interactions of the buffer and the system to be buffered. The reaction of amines or polyamines with various molecules to form polyamines with differing pKa's will extend the buffering range, derivatives that result in polyamines that have the same pKa yields a greater buffering capacity. Derivatives that result in zwitterionic buffers improve yield by allowing a greater range of stability.

DESCRIPTION OF THE FIGURES

Attention is now directed to the following figures that describe embodiments of the present invention:

Fig. 1 shows the derivation of polyamines and zwitterionic buffers from tromethamine.

Fig. 2 shows the derivation of zwitterionic buffers and polyamines from aminomethylpropanol.

Fig. 3 shows the reaction of 2-methyl-2-nitro-1 -propanol with acrylonitrile and its derivatives.

Fig. 4 shows the reaction of 2-nitro-2-ethyl-1 ,3-propanediol with acrylonitrile and its derivatives where x,y,and n are all integers where x and y are chosen independently, such that x+y=n and n is greater than zero.

Fig. 5 shows the reaction of 2-nitro-2-methyl-1 ,3-propanediol with

acrylonitrile and its derivatives where x,y,and n are all integers where x and y are chosen independently, such that x+y=n and n is greater than zero.

Fig. 6 shows the reaction of tris(hydroxymethyl)nitromethane with acrylonitrile and its derivatives where x,y, z, and n are all integers where x, y and z are chosen independently, such that x+y+z=n and n is greater than zero.

Fig. 7 shows the reaction of 2-nitro-1 ,3-propanediol with acrylonitrile and its derivatives where x,y,and n are all integers where x and y are chosen independently, such that x+y=n and n is greater than zero.

Fig. 8 shows the reaction of 2-nitro-1 -butanol with acrylonitrile and its derivatives.

Fig. 9 shows Figure 9 shows alkoxylation of aminomethylpropanol.

Fig. 10A shows the synthesis of a very mild, high foaming, surfactant derived from MCA.

Fig. 10B shows the synthesis of a very mild, high foaming, surfactant derived from SVS.

Fig. 11 shows the synthesis of a series of buffers with 2-nitropropane as the starting material.

Fig. 12 shows Figure 12 shows the synthesis of a series of buffers with 1 - nitropropane as a starting material where n and m are integers where m+n is greater than zero and n is greater than or equal to m.

Fig. 13 shows the synthesis of a series of buffers with nitroethane as a starting material where n and m are integers where m+n is greater than zero and n is greater than or equal to m.

Fig. 14 shows the synthesis of a series of buffers with nitromethane as a starting material where x,y,z and n are integers and x+y+z=n and n is greater than zero. Fig. 15 shows the synthesis of a series of zwitterionic buffers based on acrylic acids.

Fig. 16 shows the synthesis of a zwitterionic sulfonate based on

tromethamine.

Fig. 17 shows the synthesis of a zwitterionic sulfonate based on

aminomethylpropanol.

Fig. 18 - 25 show the synthesis of families of zwitterionic buffers from nitroalcohols.

Fig. 26 shows the synthesis of zwitterionic buffers from morpholine.

Fig. 27 shows the synthesis of zwitterionic buffers from hydroxyethyl piperazine.

Fig. 28 shows the synthesis of zwitterionic buffers from piperazine.

Fig. 29 shows the synthesis of zwitterionic buffers from ethyleneamines. Fig. 30 shows the synthesis of a zwitterionic buffer with primary, secondary, tertiary, or quaternary amine functionality.

Fig. 31 - 33 show the synthesis of mild zwitterionic surfactants from nitroalcohols.

Fig. 34 - 37 show the synthesis of polyamines from nitroalcohols.

Fig. 38 shows the synthesis of diamines from nitroalcohols and

aminoalcohols.

Fig. 39 shows the synthesis of isopropyl amine acrylate buffers and mild surfactants.

Fig. 40 shows the synthesis of zwitterionic buffers from SVS and MCA derived from isopropyl amine as well as mild surfactants and diamines. Fig. 41 shows the synthesis of a sultaine zwittterionic buffer of isopropyl amine.

Fig. 42 shows the synthesis of zwitterionic buffers from amino alcohols and itaconic acid.

Fig. 43 shows the synthesis of nitro acids from nitroalcohols and itaconic acid.

Fig. 44 shows the synthesis of primary amino zwitterionic buffers from nitro acids.

Fig 45. shows the synthesis of a family of zwittenonic buffers from itaconic acid and amines.

Fig. 46 shows the synthesis of surfactants from amines and itaconic acid intermediates.

Fig. 47 shows the synthesis of nitroacids from nitroparaffins and itaconic acid.

Fig. 48 shows the synthesis of zwitterionic buffers from nitro acids.

Fig. 49 shows the synthesis of zwitterionic buffers from 4-aminopyridine. Fig. 50 shows the synthesis zwitterionic buffers from the ketimine

conformation of 4-aminopyridine.

Fig. 51 shows the synthesis of zwiiterionic sultaines from 4-aminopyridine. Fig. 52 shows the synthesis of zwitterionic buffers from taurine.

Fig. 53 shows the synthesis of zwitterionic buffers from homotaurine.

Fig. 54 shows the synthesis of zwitterionic buffers from aspartic acid.

Fig. 55 shows the synthesis of sultaine zwitterionic buffers from sodium bisulfite and epichlorohydrin.

Fig. 56 shows the synthesis of sultaine zwitterionic buffers from sodium bisulfite, epichlorohydrin, and aminoalcohols.

Fig. 57 shows the synthesis of zwitterionic buffers from propane sultone

Fig. 58 shows the synthesis of amidoamine buffers from acrylamide.

Fig. 59 shows the syntheis of amidoamine buffers from methacrylamide. Fig. 60 shows the synthesis of amidoamine buffers from taurines and diamines.

Fig. 61 shows the synthesis of zwitterionic amidoamine buffers from propone sultone and SVS.

Fig. 62 shows the synthesis of sultaine amidoamine zwitterionic buffers. Fig. 63 shows the synthesis of a family of coumpounds as zwitterionic buffers and products that are expected to be useful as multiple sclerosis and spinal cord injury therapies.

Fig. 64 shows amide based zwitterionic buffers and products that are expected to be useful as multiple sclerosis and spinal cord injury therapies. Fig. 65 shows additional zwitterionic buffers based on 4-aminopyridine amides. These products are also expected to be useful as multiple sclerosis and spinal cord injury therapies.

Fig. 66 shows the synthesis of zwitterionic buffers that are also expected to be useful as multiple sclerosis and spinal cord injury therapies. Most of this family has increased hydrogen bonding and is based on the MCA derived zwitterionic buffers disclosed herein.

Fig. 67 shows the synthesis of zwitterionic buffers that are also expected to be useful as multiple sclerosis and spinal cord injury therapies. Most of this family has increased hydrogen bonding and is based on the acrylic acid derived zwitterionic buffers disclosed herein.

Fig. 68 shows the synthesis of zwitterionic buffers that are also expected to be useful as multiple sclerosis and spinal cord injury therapies. Most of this family has increased hydrogen bonding and is based on the methacrylic acid derived zwitterionic buffers disclosed herein.

Fig. 69 shows the synthesis of zwitterionic buffers that are also expected to be useful as multiple sclerosis and spinal cord injury therapies. Derived from ethylene amines.

Fig. 70 shows the synthesis of amidoamine buffers that are stearicly hindered.

Fig. 71 shows the synthesis of amidoamine buffers that are stearicly hindered with extensive hydrogen bonding.

Fig. 72 shows the synthesis of amidoamine buffers.

Fig. 73 shows that any of the amidoamine buffers taught herein, maybe reduced to aminoalcohols or diamines.

Fig. 74 shows the esterification of the zwitterionic buffers.

Fig. 75 shows the esterification, mono- and diesterification of the itaconic acid based zwitterionics.

Fig. 76 shows the synthesis of diacid, tertiary amine, zwitterionic buffers. Fig. 77 shows the synthesis of amido amines from zwitterionic buffers. Fig. 78 shows the synthesis of a variety of 4-aminopyridine derivatives that are useful buffers.

Fig. 79 shows the condensation polymerization of the hydroxyl functional zwitterionics.

Fig. 80 clarifies the amidoamine to aminoalcohol or diamine synthesis originally outlined in Figure 73.

Fig. 81 - 84 teach the synthesis of sulfonamides from the zwitterionic buffers. Fig. 85 shows the synthesis of quaternary amine salts from tertiary

aminoalcohols.

Fig. 86 -87 teach the synthesis of sulfonate esters of the zwitterionic buffers.

Fig. 88 - 89 teach the synthesis of amino acid, zwitterionic buffers with primary amine functionality.

Fig. 90 expands on the quaternary amine salts shown in Fig. 85.

Fig. 91 - 92 show the use of acrylate hydroxyesters in the synthesis of biological buffers.

Fig. 93 teaches the synthesis of a family of phosphonates and phosphonate amino acids.

Fig. 94 teaches the synthesis of a family of phosphamides.

Fig. 95 teaches the synethsis of zwitterionic buffers based on MCA and sulfonic acids.

Fig. 96 teaches the synthesis of an enzyme inhibitor.

Fig. 97 teaches the synthesis of diacid sulfonic acid buffers.

Fig. 98 teaches diacid buffers with sulfonic acid and phosphonate

functionality.

Fig. 99 teaches diacid buffers with sultaine and carboxcylic acid functionality.

Fig. 100 - 101 teach the reduction of the zwitterionic buffers to alcohols and ethers.

Fig. 102 - 104 teaches the synthesis of zwitterionic buffers and their reduction to alcohols and ethers.

Fig. 105 teaches the synthesis of sulfonamide buffers.

Fig. 106 teaches the synthesis of mono and disubtituted Michael additions to form zwitterionic buffers.

Fig. 107 teaches the synthesis of a new class of amines and aminoalcohols and their derivatives.

Fig. 108 teaches the synthesis of a new class of amines and aminoalcohols and derivatives of nitro compounds and valeraldehyde.

Fig. 109 teaches the synthesis of a new class of aminoalcohols and their derivatives based on monosubtitution of gluteraldehyde and nitro compounds. Fig. 110 - 111 teaches the synthesis of diamines and their derivatives based on gluteraldehyde and nitro compounds.

Fig. 112 - 113 teach the synthesis of a class of amino alcohols derived from glucose and nitro compounds and their derivatives.

Fig. 114 -115 teach the synthesis of banzaldehyde and nitro compounds and their derivatives.

Fig. 116 teaches how dimmers can be formed when using a nitro compound with more than one hydrogen on the nitro containing carbon.

Fig. 117 teaches how dialdehydes can be used to make dimmers and polymers.

Fig. 118 teaches a novel route to nitro acids and primary amino acids of several types.

Fig. 119 teaches the synthesis of surfactants based on aldehydes and nitro compounds.

Fig. 120 expands Figure 107 to cover an additional species where the aldehyde is acetaldehyde in which E -CH ₃ .

Several drawings and illustrations have been presented to aid in

understanding the invention. The scope of the present invention is not limited to what is shown in the figures.

DETAILED DESCRIPTION OF THE INVENTION

Combining amines with monochloroacetic acid (MCA)or sodium vinyl sulfonate (SVS) results in products are zwitterionic buffers that can buffer in both acidic and basic pH conditions. A limited number amines are currently used for this purpose, such as, tromethamine and ammonia. The reaction of amines, alcohols, and aminoalcohols with acrylonitrile (via the Michaels Addition), followed by reduction results in amines and polyamines that have a broad buffering range. The further de vatization of the amines and polyamines with MCA and SVS yields a further crop of amine buffers with desirable properties. One skilled in the art will recognize that MCA and sodium monochloroacetic acid (SMCA) can be used interchangeably.

The reaction of tromethamine as described above yields the products in Figure 1 . In step 1 in Figure 1 where the acrylonitrile is added to the amine a branched structure wherein the addition of acrylonitrile results in a tertiary amine is shown. In reality, particularly when n is greater than 1 , a mixture of products is obtained that is both tertiary and secondary. For the invention disclosed herein, n may equal any integer greater than zero, including 1 . Controlling the reaction temperature, pressure and agitation will allow the mixture to be predominately secondary (such as when m=n) or tertiary amine, m can be any integer less than or equal n. Furthermore, this selection can take place in adding acrylonitrile to the amine that results, allowing a progressively more branched product. It is within the scope of the invention disclosed herein to include these additional types of products and their subsequent derivatives described herein.

With regard to the reaction of the polyamine resulting from the second step in Figure 1 . Figure 1 shows the addition of only one mole of SVS or MCA, it is known in the art, that a second mole may be added to obtain a product with a second zwitterionic group. Furthermore, in the case where the product has repeated additions of acrylonitrile and reduction to the amines, the branched products may have many more zwitterionic groups. Also, it is to be noted that, while the sulfonates are shown as sodium salts, other salts and the free acids (non-salted form) are also within the scope of this invention.

Other amines that would make excellent starting materials in place of tromethamine are 2-amino-2-methyl-1 -propanol, 2-amino-1 -butanol, 2-amino-2-ethyl- 1 ,3-propanediol, 2-amino-2-methyl-1 ,3-propanediol, and

dihydroxymethylaminomethane.

Additionally, fatty amines, such as lauryl amine, coco amine, tallow amine, and oleoyl amine, and fatty ether amines, such as bis-(2-hydroxyethyl) isodecyloxypropylamine, when reacted with SVS produce mild surfactants that find utility where zwitterionic surfactants are desired, including personal care.

Other amines that are shown in Figure 2 are produced via a similar series of reactions, except that figure 2 includes zwitterionic buffers from the amine 2-amino-2- methyl-1 -propanol, as well as the polyamines derived from the reaction with acrylonitrile and the subsequent derivatives described above. Other amines can be utilized in addition to 2-amino-2-methyl-1 -propanol to obtain excellent buffers are 2- amino-1 -butanol, 2-amino-2-ethyl-1 ,3-propanediol, 2-amino-2-methyl-1 ,3- propanediol, and dihydroxymethylaminomethane. Reaction conditions could be created such that the alcohol groups on the amines listed above could be reacted with acrylonitrile as well, and then reduced to the amines and, if desired, reacted with SVS or MCA to impart zwitterionic character.

Polyamines with good properties for use in biological fermentations, purifications, storage and general handling can also be produced through the reaction of nitroalcohols and acrylonitrile, followed by reduction. Additional derivatization with SVS or MCA will result in zwitterionic buffers with a very large buffering range and capacity.

Figure 3 shows the reaction of 2-methyl-2-nitro-1 -propanol with acrylonitrile and its derivatives.

Figure 4 shows the reaction of 2-nitro-2-ethyl-1 ,3-propanediol with acrylonitrile and its derivatives where x,y,and n are all integers where x and y are chosen independently, such that x+y=n and n is greater than zero.

Figure 5 shows the reaction of 2-nitro-2-methyl-1 ,3-propanediol with

acrylonitrile and its derivatives where x,y,and n are all integers where x and y are chosen independently, such that x+y=n and n is greater than zero.

Figure 6 shows the reaction of tris(hydroxymethyl)nitromethane with

acrylonitrile and its derivatives where x,y, z, and n are all integers where x, y and z are chosen independently, such that x+y+z=n and n is greater than zero.

Figure 7 shows the reaction of 2-nitro-1 ,3-propanediol with acrylonitrile and its derivatives where x,y,and n are all integers where x and y are chosen independently, such that x+y=n and n is greater than zero.

Figure 8 shows the reaction of 2-nitro-1 -butanol with acrylonitrile and its derivatives.

Figures 2 through 8 are subject to the same clarifications as figure 1 with regard to the cyanoethylation and the formation of a more linear or branched structure as well as the addition of SVS or MCA in molar equivalents of primary amine groups or less than molar equivalents of primary amine groups present.

The buffers described thus far may also be ethoxylated, propoxylated, or butoxylated to modify their properties. Ethoxylation will tend to impart surfactancy to the resulting product. Propoxylation will add surfactancy, but also reduce the water solubility. This is useful in emulsion breaking and reverse emulsion breaking, this will also find utility in breaking up and dissolving biofilms. This is also desired in oilfield applications. Butoxylation will similarly shift the HLB to the hydrophobic.

Combinations of ethoxylation, propoxylation, and butoxylation can be tailored to specific emulsion and reverse emulsion forming and breaking requirements. Figure 9 shows alkoxylation of aminomethylpropanol. The direct 2 mole ethoxylation of 2- amino-2-methyl-1 -propanol with 2 moles of ethylene oxide, as shown in Figure 9 produces an excellent biological buffer with less chelation than 2-amino-2-methyl-1 - propanol. The reaction of 2-amino-2-methyl-1 -propanol with propylene oxide or butylene oxide yields a similarly less chelating product, as does the reaction with diethylene glycol. The reaction product of 2-amino-2-methyl-1 -propanol with 1 mole of diethylene glycol as shown in Figure 9 produces an ideal amine for gas scrubbing of H ₂ S. This product is particularly useful because it does not bind to carbon dioxide and carbon monoxide in any appreciable amount. Thus making it ideal for tail gas scrubbing and maximizing the capacity of sulfur plants in refineries. Similar performance is seen with the reaction of the following amines 2-amino-1 -butanol, 2- amino-2-methyl-1 ,3-propanediol, 2-amino-2-ethyl-1 ,3-propanediol,

tris(hydroxylmethyl)aminomethane, and 2-amino-1 ,3-propanediol.

The buffers described herein also make excellent starting materials for surfactants. Figure 10 shows the synthesis of 2 very mild, high foaming, surfactants that are well suited for personal care applications were irritation is problematic, such as baby shampoo and face cleansers. Similar results are seen when 2-amino-1 - butanol, 2-amino-2-methyl-1 ,3-propanediol, 2-amino-2-ethyl-1 ,3-propanediol, tris(hydroxylmethyl)aminomethane, and 2-amino-1 ,3-propanediol are used as the starting material in place of 2-amino-2-methyl-1 -propanol.

Polyamines with good properties for use in biological fermentations, purifications, storage and general handling can also be produced through the reaction of nitroalkanes and acrylonitrile, followed by reduction. Additional derivatization with SVS or MCA will result in zwitterionic buffers with a very large buffering range and capacity. Figure 1 1 shows the synthesis of a series of buffers with 2-nitropropane as the starting material. Figure 12 shows the synthesis of a series of buffers with 1 -nitropropane as a starting material where n and m are integers where m+n is greater than zero and n is greater than or equal to m.

Branching can be imparted on the buffers described in figures 1 1 through 14 for the polyamines that have greater than 3 amine groups by reducing the resulting nitrile or polynitrile to the polyamine and then reacting with more acrylonitrile and then reducing the resulting nitrile groups to amine groups. This can be done repeatedly. As in Figure 1 , conditions can be chosen such that a more branched product results. A more linear product is produced by simply adding all the acrylonitrile in one step, and then reducing the resulting polynitrile to the polyamine. For figures 12 through 14, the zwitterionic products can be made by adding MCA or SVS as shown in Figures 2 through 8.

Figure 13 shows the synthesis of a series of buffers with nitroethane as a starting material where n and m are integers where m+n is greater than zero and n is greater than or equal to m. Figure 14 shows the synthesis of a series of buffers with nitromethane as a starting material where x,y,z and n are integers and x+y+z=n and n is greater than zero.

Several descriptions and illustrations have been presented to enhance understanding of the present invention. One skilled in the art will know that numerous changes and variations are possible without departing from the spirit of the invention. Each of these changes and variations are within the scope of the present invention. Another embodiment of the present invention is the synthesis of zwitterionic buffers with vinyl acids. Figure 15 shows the synthesis of a family of zwitterionic buffers based on members of the acrylic acid family. However, other vinyl acids may be used. Vinyl acids such as acrylic, 3-butenoic acid, 4-pentenoic acid, and other carboxcylic acids with a double bond at the terminus. Carboxcylic acids with a triple bond at the terminus also can be utilized, similarly, an acid where the multiple bond is not at the terminus, such as hex-4-enoic acid, can also be utilized. However, due to the reduced commercial availability of such compounds, the preferred embodiment is the vinyl acid with a double bond at the terminus. One very large benefit of utilizing vinyl acids to make zwitterionic buffers is that the product does not need to be ion exchanged to produce a non-ionized form. In the market, both ionized, or sometimes called salted, and non-ionized forms sometimes called free acid or free base, are required. In situations where ionic strength must be very closely

controlled, the non-ionized forms are more popular. For cases where increased water solubility and ease of solution are desired, the salted forms are preferred. It is understood to one skilled in the art, the present invention covers both the ionized and non-ionized forms of the buffers disclosed herein.

Another embodiment of the present invention is the sulfonate zwitterionic buffers derived from the reaction of an amine with an epichlorohydrin and sodium bisulfate condensate as described in Figure 16. It is understood by one skilled in the art that other sulfate salts can be utilized to arrive at the desired molecular structure and is included in the present invention. Figures 17 through 25 teach the flexibility of the present invention to synthesize a series of a amine sulfonate or amino acid zwitterionic buffers from nitroalcohols or alkanolamines to produce zwitterionic buffers that have primary amino functionality or secondary amino functionality. In cases where there are more than one reactive group, amine, alcohol, or a

combination, multiple sulfonate groups or acid groups can be reacted by adding more than one equivalent of the vinyl acid or the oxirane containing sulfonate.

Another embodiment of the current invention is to make zwitterionic buffers with cylcoamines as the starting material. The cycloamines result in a tertiary amino group that is less chelating and interferes less in biological functions. Figure 26 shows the reaction of morpholine with a vinyl acid and morpholine with the oxirane sulfonate. Figure 27 shows similar products, but utilizing hydroxyethyl piperazine. Figure 28 shows the use of diamines as starting materials by using piperazine as the starting material. This is a good example of a synthesis of polyzwittterionic buffers as discussed earlier. Figure 29 shows the use of ethylene amines to make zwitterionic buffers through reaction with vinyl acids or oxirane sulfonates. One skilled in the art will recognize that similar compounds can be made by using ethylene amines, such as monoethanolamine and the higher homologs, such as diethylenetriamine and is part of the invention disclosed herein.

Another embodiment of the current invention is the synthesis of zwitterionic amines that have primary, secondary, tertiary, and quaternary amine functionality. Figure 30 shows this via oxirane sulfonate and amines. One skilled in the art will recognize that any primary, secondary, or tertiary amine can be used in place of the methyamines in Figure 30. While not shown in the figure, one skilled in the art will recognize that the resulting amines can be reacted further with vinyl acids, monochloroacetic acid, sodium vinyl sulfonate, or an oxirane sulfonate to further add acidic character to the zwitterionic buffer.

Another embodiment of the current invention is the synthesis of mild surfactants from nitroalcohols. Figures 31 through 33 teach the synthesis of these mild surfactants. Lower molecular weight acids produce lower foaming mild surfactants, whereas higher molecular weight carboxcylic acids yield higher foam. Laurie acid is the preferred embodiment for a high foaming, mild surfact. Coconut fatty acid performs similarly, but at a lower cost. A good surfactant with low foam can be made using octanoic acid as the carboxcylic acid.

Another embodiment of the current invention is the synthesis of polyamines from nitroalcohols. Figures 34 and 35 teach the synthesis of diamines from nitroalcohols. Figure 34 shows the synthesis with several hydroxyl groups present. It is understood by one skilled in the art that additional amino groups can be added by reacting more than one equivalent of epichlorohydrin to the nitroalcohol, up to the number of hydroxyl groups, and then reacting the same number of equivalents of amine to the oxirane containing amine. In the case where the nitroalcohol is reduced to the amino alcohol in the beginning, the addition of base, such as caustic, to the amino alcohol will assist in the reaction of the epichlorohydrin with the hydroxyl groups. Without the base, the epichlorohydrin will preferably react with the amine as outlined in the 1 equivelent addition depicted in Figure 34 and Figure 35. Figure 36 demonstrates that tertiary amines can be used to make zwitterionic buffers with quaternary amine functionality from tertiary amines. While not explicitly shown, any other tertiary amine can be used as the starting material and is part of the invention described herein. Figure 37 and Figure 38 demonstrate that diamines can be made from nitroalcohols by reacting sequentially the nitroalcohol with epichlorohydrin and then the second equivalent of the nitroalcohol, followed by reduction. Also taught is that a reduction step can take place in the beginning to yield a diamine with two secondary amino groups. It is understood by one skilled in the art that the

nitroalcohols or alkanolamines do not need to be symmetric, but others may be used in the synthesis of the diamine and is part of the invention disclosed herein.

Figure 42 shows the synthesis of zwitterionic biological buffers from amino alcohols and itaconic acid. These buffers have two acid groups and increased buffering in the acidic range of pH 3 - 6. Figures 43 and 44 show the synthesis of zwitterionic buffers with primary amine groups. These buffers are preferred in applications such as personal care where secondary amines are seen as

undesirable. The nitro diacids of Figure 44 also have great utility as chemical intermediates when synthesizing bioactive molecules.

Figure 45 shows the synthesis of a family of zwitterionic buffers from itaconic acid. The buffers in Figure 45 are not limited to amino alcohols as starting materials and provide a wide range of molecular size and solubilities.

Figure 46 shows the synthesis of a family of amphoteric surfactants. These surfactants are preferred for there mildness, ability to perform in hard water conditions and persistent lather when in the fatty tail is approximately 10 - 12 carbons in length. The R group in figure 46 is to encompass the fatty acid family of carbon chain lengths, generally from about 6 to about 22 carbons. In the specific cases illustrated of lauric amine and lauric dimethyl amine reacted with itaconic acid, it is understood by one in the art that any chain length amine can be used and is in within the scope of the invention herein. Particularly, but not limited to the fatty amines (carbon lengths of about 6 to about 22 carbons, branched and linear, saturated and unsaturated), isopropyl amine and butyl amine. The lower carbon chain lengths produce low foaming hard surface cleaners, while the carbon chains of about 8 to 10 tend to produce the most foam. Higher chain lengths find utility as mineral collectors in floatation processes such as those employed in iron and potash mining.

Figure 47 shows the synthesis of nitro acids from nitroparaffins. As stated early, these are very flexible intermediates, particularly when synthesizing bioactive molecules. Reduction of the nitro acids, as shown in Figure 48 produces zwitterionic buffers with primary amine character. In the case of nitroparaffins that have more than one hydrogen bound to the nitro bound carbon, more than one addition of the itaconic acid can occur. The substitution can occur up to the number of hydrogen atoms bound to the nitro bound carbon.

Figure 49 shows the synthesis of zwitterionic buffers from 4-aminopyridine, Figure 50 shows using the less stable ketimine conformation as the starting material. Figure 51 shows the synthesis of sultaine type buffers from 4-aminopyridine.

Additional buffers can be made by propoxylating and butoxylating 4-aminopyridine. The ethoxylating and propoxylating will reduce the water solubility and reduce the bioavailability. This is one method of extending the time a material is bioavailable by making it available slowly, particularly if the molecule is metabolized. Additionally, a triamine can be made by reacting 2-aminopyridine with arcrylonitrile and reducing it to the triamine, or reacting with allylamine to keep the aromatic nature of the six membered ring. The resulting buffers are excellent buffers in their own right, but also have great promise in treatment of multiple sclerosis, and other conditions that can benefit from calcium or other cation inhibition. The anionic components, in particular, are all groups that can chelate cations.

Figure 52 outlines the synthesis of taurine derived zwitterionic buffers. These molecules, along with the products in Figure 53, homotaurine derived zwitterionic buffers, are expected to find great utility in the purification of proteins and in cell culture media. Figure 54 shows the synthesis of a series of zwitterionic buffers derived from aspartic acid. These compounds are expected to be very useful in electrophoresis gels as they have a unique charge density and size profile. The sultaine derivatives in Figure 55 and Figure 56 are expected to find great utility in cell culture media and in purification due to their zwitterionic nature and pKa range. The zwitterionic buffers of Figure 57 are expected to be primarily useful in cell culture media. The buffers of Figure 58 and Figure 59 are ideally suited for use in

electrophoresis gels and in isoelectric focusing. Figure 60, Figure 61 and Figure 62 show the synthesis of zwitterionic amidoamine buffers for use cell culture media and purification.

Figure 63 shows the synthesis of zwitterionic buffers that are expected to be useful in the treatment of multiple sclerosis (MS) and spinal cord injury by blocking potassium channels. The increased hydrogen bonding available through the sulfonate group is expected to enhance the efficacy over the traditional 4- aminopyridine therapy. While the figure shows only two compounds, one skilled in the art will recognize that any of the amino acid taurates, including, but not limted to those disclosed herein, particularly those of Figures 52, 53, 54, and 57. Figures 64 and 65 show the synthesis of a further class of amidoamine buffers that are expected to be effective therapies for MS and spinal cord injury due to the pKa and hydrogen bonding. Figures 66-68 shows the synthesis of a class of compounds that are excellent amidoamine buffers, particularly useful for electrophoresis and protein focusing. These are also expected to be excellent therapies for MS and spinal cord injury through potassium channel blocking. The more hydrogen bonding variants are expected to have greater efficacy. Figure 69 shows the synthesis of a further class of amidomine buffers that are also expected to have utility as MS or spinal cord injury therapies. One skilled in the art will recognize that the amino acids used are not limited to those presented but any amino acid can be utilized and are within the scope of the present invention. In particular, the analogs based on methacrylic and other vinyl acids as the amino acid reacted with 4-aminopyridine are within the scope of the present invention, similar to the analogs presented in Figure 15 where tromethamine is reacted with various acids to form a family of amino acids. Figures 70-72 teach a family of amidoamine buffers. Figure 73 shows that any of the amidoamines presented herein, may be reduced to the aminoalcohol by reacting with hydrogen in the presence of a catalyst, such as raney nickel or raney cobalt, as well as reduced to the diamine by treatment with lithium aluminum hydride or similarly strong reducing agent.

As outlined earlier, one skilled in the art will recognize that the resulting amines can be reacted further with vinyl acids, monochloroacetic acid, sodium vinyl sulfonate, or an oxirane sulfonate to further add acidic character to the zwitterionic buffer. One skilled in the art will recognize that the salts and free acids and free bases of the compounds taught herein are within the scope of the invention.

Additionally, to adjust the water solubility, it is useful to alkoxylate of the buffers taught herein, particularly with ethylene oxide, propylene oxide or butylenes oxide or a combination of alkoxylating agents in any amount or ratio to reach the desired result. The resulting alkoxylates will in some cases produce surfactants. Another way to make mild surfactants from the buffers taught is to esterify. Figures 74 and 75 show the esterification of the mono- and di- acid functional zwitterionics. It is understood by one skilled in the art that all the zwitterionics taught herein may undergo this reaction in a similar fashion to those explicitly shown. For example, the Figures 74 and 75 do not explicitly show the esterification of the products of Figure 26, but it is understood that the esterification is similar enough to be recognized by one skilled in the art. The 4-aminopyridine derived zwitterionic buffers benefit from esterification in adjusting the bioavailability and water solubility, much as they do from alkoxylation, to improve their efficacy and reduce side effects when used as a therapy for MS, Alzheimer's disease, or other medical use.

The primary amines that are the basis for the zwitterionic buffers, may undergo disubstitution to form diacid functional buffers as shown in Figure 76. These may be mono- or diesterified just as the itaconic acid based buffers in Figure 75. Figure 77 expands on the amidoamines that can be synthesized from the zwitterionic buffers. The amidoamine formation may also be carried out by diamines to create dimmers, or with the secondary diamines, such as coco diamine or tallow diamine to produce surfactants that act as corrosion and scale inhibitors. Figure 78 shows the synthesis of a variety of 4-aminopyridine derivatives that are useful buffers. The varying amine strength and water solubility give them unique properties.

Figure 79 shows the condensation polymerization of the hydroxyl functional zwitterionic buffers. As shown, linear polyesters or polyester prepolymers are produced. By using the buffers with varying hydroxyl numbers, a hydroxyl functional polymer results. When used as a prepolymer, greater cross-linking can be introduced when incorporated into a polyurea, polyurethane, or polyether. If condensed with the itaconic based buffers, such as those in Figure 42, or other polyacid functional monomers or prepolymers, a 3 dimensional polyester polymer matrix can be achieved.

Figure 80 further clarifies the ability to make diamines from the amides taught herein. In Figure 80, where G is -OH, it can either remain intact when done under milder reduction conditions, or be converted to -H when harsher conditions, such as when LAH is used. The most useful of these amidoamines and diamines is expected to be those where A=D=E=M=J=L=-CH ₂ OH.

Figures 81 , 82, 83 and 84 demonstrate how the sulfonate buffers can be converted to sulfonamides. Sulfonamides have a wide range of known biological activity and these sulfonamides are expected to have increased antimicrobial properties versus their related sulfonates or carboxcylic acid functional zwitterionics.

It is well known in the art that sulfonamides can be reduced under mild conditions to the suflonimides, which are within the scope of the invention disclosed herein.

Figure 85 shows the synthesis of quaternary amine salts. These products are particularly useful in diagnostic kits for condution, as well as there antimicrobial properties. The case where A=-CH ₂ OH and D=E=R=R'=-CH ₃ is the most useful of this class, but the other permutations are useful when the water solubility needs to be increased or decreased.

Figures 86 and 87 teach the synthesis of sulfonate esters from the zwitterionic buffers. These esters allow for changing the water solubility, while maintaining buffering capacity. Figures 88 and 89 teach the synthesis of zwitterionic buffers with primary amino functionality. Again, the 4-aminopyridine moiety containing buffers are promising targets for therapies to treat MS and potentially Alzheimer's disease or other diseases that involve demyelination or other myelin anomalies.

Fig. 90 expands on the quaternary amine salts shown in Fig. 85.

Figs. 91 and 92 show the synthesis of buffers with adjusted HLB by using hydroxyesters of acrylic acids. In Fig. 91 , an example of a disubstituted amine is shown in the second line. This applies for all the amine and acrylate pairs which are within the scope of the present invention. Fig. 91 , in addition to showing the hydroxyester acrylates which can be made through acid catylized esterification of the acrylic acid, also show an alkoxylated acrylate. The alkoxylated acrylate can be prepared through acid catalyzed alkoxylation utilizing ethylene oxide, propylene oxide, butylene oxide or any other alkoxylate. The reaction product is a buffer that possesses a wide range of water solubilities. Fig. 91 includes this process.

Fig. 93 teaches the synthesis of phosphonates based on aminoalcohols and amino acids, as well as those derived from 4-Aminopyridine. These phosphonates are excellent buffers in their own right, but have other benefits. The phosphonates have a higher solubility profile when salted with divalent cations, such as, calcium, magnesium and zinc. This also results in the molecules being excellent chelants and scale inhibitors. In addition, these phosphonates are expected to be quite

biologically active. The amino acid starting materials in Fig. 93 exhibit fungal resistance as well as resistance moss, mold and some bacteria. The 4- Aminopyridine derivatives are biologically active as treatments for MS and other autoimmune diseases, such as rheumatoid arthritis, and conditions effected by abnormal myelination. The phosphonates are expected to extend this efficacy further. In addition, the phosphonates, of the amino acids in particular, are expected to be excellent herbicides.

The phosphamides of Fig. 94 show great promise as insecticides and insecticide precursors. These phophamides also show promise as chemotherapy agents for treatment of cancers. It is believed that the phosphamides taught are useful therapies for autoimmune diseases by suppressing the immune response to various antigens. Figure 95 teaches the synthesis of zwitterionic sulfonates based on monochloroacetic acid. Figure 96 teaches an enzyme inhibitor. Figure 97 through Figure 99 teach the synthesis of diacid buffers. These buffers, while useful as buffers also possess unique biological properties, including enzyme inhibition. Thus making these very useful tools in agriculture, diagnostics, and biotechnology. It is understood by one skilled in the art that the amino acid starting materials could be substituted for their esters or alkoxylates, such as in figures 74, 86, 91 , 92, thus giving the analogous products.

Figure 100 outlines a family of products that are useful buffers that are primarily liquid and distillable. These products also have wider applications, specifically in removal H ₂ S from both refinery processes as well as gas and liquid petroleum, products. The reduction of the carbonyl produces compounds that are more stable to the harsh conditions seen in oil and gas recovery and refinery processes. The final molecule at the bottom of Figure 104 is a hindered amine that has fewer interactions than the primary amine with proteins, improving yield when used to purify proteins. It is a suitable H ₂ S treating amine as well. Lines 2, 4, and 6 of Figure 100 are present simply to underscore the fact these amines used as precursors may be mono or disubstitued, as made clear in other sections. This is true for all the primary amine starting materials and the resulting products and the downstream derivatives that result are included within the scope of this invention. Figure 101 continues to teach the reduction of the zwitterionic buffers and their esters to alcohols and ethers. For the sulfonic acid zwitterions, if the reduction is allowed to run longer or is run under stronger reducing conditions, such as with LAH, the sulfonic acid groups will be converted to thiols. These thiols are also within the scope of the present invention.

Figure 102 teaches the synthesis of a range of zwitterionic buffers based on dopamine. These products, and there derivatives are excellent buffers in their own right, but also posses bioactivity, including fungal resistance. Figure 103 includes sulfonamides that are particularly fungal resistant, as are the zwitterionic buffers taught. Figure 104 primarily teaches the synthesis of dopamine based zwitterionic buffers and their esters. The esters expand the usefulness of the product by resulting in more hindered buffers so that there are less interactions with proteins that can destabilize their tertiary structure. Figure 105 teaches the synthesis of sulfonamide and disulfonamide buffers based on the zwitterionic buffers previously taught. In addition to their buffer capability and utility in protein fermentation and purification, the sulfonamide buffers, particularly those based on 4-aminopyridine and dopamine, are expected to have use as therapeutic agents in areas where fungal infection is part of the condition.

Figure 106 demonstrates again the mono or disubtitutions that can take place with primary amines. Both species and there analog derivatives that are taught in this application are within the scope of the present invention. The sulfonic acid buffers may also be synthesized as diacids analogous to the carboxcylic acid diacid analogs in lines 1 and 2 of figure106. They are not explicitly shown because it is obvious to one skilled in the art that these molecules are part of the invention.

Figures 107 through 1 15 and Figure 120 teach the synthesis of a new class of amines and aminoalcohols, as well as a range of derivatives that are suitable as buffers, monomers antimicrobials, and dispersants. Taught are secondary amino acids based on monochloroacetic acid and acrylic acid type monomers and their esters for both classes, sulfonates, phosphonates, alkoxylates, and polyamines based on acrylonitrile. While not shown in the figures in every case, the esters (standard esters, phosphate esters, phosphonate esters, and sulfonate esters) of these compounds that result from the reaction of alcohols or polyols are also within the scope of this invention, for linear, branched, saturated or unsaturated alcohols, including polyols such as, but not limited to, EG, PG, BG and polymers or block copolymers. These derivatives have been adequately within this patent application such that they are included within the scope of this invention.

While in the Figures, mainly the monosubstitution on the primary amine is shown for each type of derivative, it is part of this invention to include the

disubstitution, analogous to what is shown in Figure 76 and similarly throughout this patent application. It is worth pointing out that when reacting acrylonitrile with the nitroalcohols, The secondary alcohol reacts less quickly than the primary alcohol, when present, when A and / or D include a primary alcohol group, as well as the primary alcohol in all molecules in Figure 109 where the amine starting material for the derivatives contains a primary alcohol. The reaction proceeds analogous to the secondary alcohol shown, as does the reduction, if pursued. An excess of acrylonitrile reacts both the primary and secondary alcohols and at even greater levels, forms nitrile polymer. The primary alcohol groups will also undergo

monosubstituted alkoxylation, but at a slower rate than the amine, Less reactive conditions, such as lower temperatures can limit the alkoxylation to the amine. The alkoxylation of the alcohol groups is also part of the invention described.

In the case of the sulfonates, SVS is the only reactant shown, however, the analogous reaction with propane sultone is included as part of this invention. The result, as taught by analogy earlier in this patent application, is an additional carbon between the reactive amine and the -S0 ₃ H group.

Figure 1 10 teaches the synthesis of primary diamines from gluteraldehyde and nitro compounds. The figure focuses on the monosubtitution of both of the primary amine groups., However, the invention includes the monosubstitution of just one amine, the disubstitution of both amines, and the disubstitution of one amine and monosubstitution of the other. Further, the invention includes the derivatives where one type of derivative is made on one amine, and another of the described derivative types is made on the other. Likewise, as shown in figure 93, the derivations can vary on the individual amine and still be within the scope of this invention. Figure 1 1 1 is a continuation of Figure 1 10 in that it teaches more derivatives of the gluteraldehyde based diamines and dinitro compounds. Specifically, alkoxylation and acrylonitrile derivatives.

Figure 1 12 teaches the synthesis of a group of aminoalcohols based on glucose. While glucose is taught explicitly in this Figure, all aldehyde terminated sugars can be treated the same way as glucose to yield the analogous amines.

Other aldehyde terminated sugars included in this invention, but not limited to are allose, altrose, mannose, gulose, arabinose, xylose, fucose, idose, galactose, talose, ribose, arabinose, xylose, lyxose, erythrose, threose, glyceraldehyde, glycolaldehyde and the related lactic aldehyde. In addition to sugars, flavoring aldehydes and fragrance aldehydes, such as, but not limited to, vanalin,

cinnamaldehyde (including butyl and amyl), anisic, 2,4-heptanedienal,

isovaleraldehyde, and citral may undergo this same transformation to make these novel aminoalcohols and their derivatives. It is worth noting that stereochemistry has no effect on this reaction, and therefore all stereo conformers are within the scope of this invention. Where a chiral center is introduced through the formation of the nitroalcohol, the results are racemic, and no stereochemistry in conveyed, nor implied in the structures presented. Figure 1 19 expands the invention to make surfactants by reacting glucose, or other aldehydes or aldehyde sugars with the nitro compounds of Figure 107 and Figure 120. The invention is not limited to the surfactants from the sugar aldehydes alone, but may be reacted with any of the aldehydes disclosed in this invention, as are the similar derivatives, such as the zwitterionics and phosphonates, which are also taught and within the scope of the invention. The zwitterionic derivatives make very mild, high foaming surfactants that also hold promise as mineral collectors in mining, such as iron ore and other minerals. If D is -H, then a second substitution of the E containing hydroxyl moiety can be achieved, leading to the analogous surfactant with a generally more

hydrophobic character. Naturally, these may be reacted with acrylonitrile and reduced to amines or alkoxylated analogously to the glucose or aldehyde sugar aminoalcohols in Figure 1 13. As in earlier forms, it is worth pointing out that the zwitterionic surfactants may be mon- or disubstituted at the amine with the acidic functionality. Figure 1 13 expands on Figure 1 12 by teaching the acrylonitrile and alkoxylate derivatives. For the alkoxylation, the reaction can be significantly isolated to the primary amine group is shown in the first line, however, more aggressive reaction conditions will cause the hydroxyl groups to undergo alkoxylation as well. Leading to a mixture of products. Additionally, it is common among alkoxylators to block coploymerize by reacting with one alkoxylating agent, such as EO, then another, such as PO or BO and repeat the process to achieve the desired HLB. This results in a wide range of products as alkoxylations of this type are not precise and do not yield a single product. This block copolymerization is within the scope of this invention for this and all alkoxylations taught. Further, the primary amine may be retained by performing the alkoxylation on the nitro compound that results in the first line of Figure 1 12. After the alkoxylation is complete, the nitro group can be retained, or reduced to the primary amine. Similarly, the reaction with acrylonitrile on the primary amine forming the diamine (which can be derivatized by any of the methods disclosed and included as part of this invention) can also occur on the alcohol groups under more aggressive conditions. Similarly, by reacting the nitro compound with acrylonitrile, the hydroxyls will react with the acrylonitrile, more equivelents of acrylonitrile will result in more hydroxyls being substituted, which can be isolated and used as a reactive intermediate, or reduced to the polyamine. This course produces a high yield of primary amines, verses the secondary and primary amine groups that result from reacting the acrylonitrile with the primary amine. Again, these polyamines undergo the same derivitations as taught in this invention for the other classes of amines taught. Figure 1 14 teaches the synthesis of and derivatives of

benzaldehyde and nitro compound amines. Again, the alkoxylation can be done on the amine, and largely isolated to the amine, or under more aggressive conditions, on the hydroxyls as well. If alkoxylating the nitro compound, the alkoxylation will be isolated to the alcohol groups present. Reduction of the alkoxylated nitro compound will yield a primary amine. Due to the chiral nature of many of these molecules and their derivation from natural molecules, in addition to being excellent buffers, they are expected to be useful in pharmaceutical and other life science applications as part of drug delivery systems, and some, as therapeutic agents themselves.

Figure 1 15 is a continuation of Figure 1 14 and teaches the acrylonitrile derivatives. As is the case in previous cases, the acrylonitrile addition can be isolated to the primary amine, mono (shown) or disubstituted, or under more aggressive conditions, also react with any hydroxyls present. The resulting nitrile compounds can readily be reduced to their amine counterparts. Reacting the nitro compound, will result in the hydroxyls being substituted, which can then be reduced, along with the nitro group, which will produce in high yield primary amines and minimal secondary amine formation. These amines can then undergo all the derivatives taught in this invention utilizing the aminoalcohols and are part of this invention.

Figure 1 16 - 1 17 teach the synthesis of dimmers, trimers and polymers when at least two hydrogens are present on the nitro containing carbon, and how polymers may be produced. When more than one hydrogen is present on the carbon containing the nitro group, polymerizartion is always a concern. However, controlling the addition order, rate and temperature can prevent polymer formation. Many of the methoxy containing products can be made by reacting the remaining hydrogen(s) with formaldehyde prior to the reduction to the amine, but using the nitroalcohol is preferred as it leads to much less polymer formation. Particularly in cases where the reaction conditions can not be well controlled. The amines and polyamines taught in the figures are able to undergo all the derivations taught and are part of this invention. Including, but not limited to aminoacid products sulfonic acid products, phosphates, phosphonates, polyamines via acrylonitrile, and alkoxylation. Figure 1 18 teaches a novel route to primary amino acids of several types and their nitro precursors. Again, monosubstitution is taught, but the substitution can by di- or tri if sufficient hydrogens are present in the starting nitro compound.

A great deal has been said about the nature of the primary amines that are starting materials for the invention may undergo mono or disubstitution, as shown in Figure 76. While much of the disclosure focuses on the mono substituted species for clarity, the disubstituted species for each class of molecule or derivative are fully part of this disclosure and their analogous derivatives that have been taught. Further, for all transformations taught, it is within the scope of this invention to include the monosubstituted derivative, then derivatized with another method taught, such as is shown in Figure 93, line 3 where the amine starting material is the monosubstituted amino acid made with MCA, then the second substitution is made as a phosphonate.

An additional use for the molecules taught herein is the use in print media to reduce bronzing, similar to that taught in US Patent application 12/248,323, which is incorporated by reference. Additionally, the bioactive nature of these molecules makes many of them antimicrobial in nature. The use of these molecules,

particularly, but not only, the carboxcylic acid functional molecules and there salts show this property under a wide range of conditions. The use of the molecules disclosed in this invention are also known to exhibit synergistic antimicrobial properties when used in combination with other known antimicrobials. The

antimicrobials known to show synergy include, but are not limited to isothiazolinones, carbamates, formaldehyde condensates, formaldehyde donors, phenols, parabens, quaternary ammonium compounds, methylenes, metals and their organic salts, halogenated organics and inorganics, hexetidine, phthalates, sulfonamides and all other antimicrobials. In addition to the other uses for the invention described are as gas scrubbing amines for removal of acid gases, such as C0 ₂ , H ₂ S, CO and other acidic gases from industrial processes. They can be used alone, or in combination with other amines, solvents, and all other known means of removing acid gases. Further application of the molecules disclosed herein is the use as dispersants for minerals, pigments, chelation of cations, corrosion inhibition, and the prevention of scale formation. The molecules taught also have great potential as herbicides or adjuvents, particularly when used with other adjuvents, but also alone. Adjuvents that are expected to increase the efficacy, weather used alone or in combinations that may include other surfactants, solvents, or coupling agents include alcohols, amines, ethyleneamines, alkoxylated amines, alkoxylated alcohols, ether amines, alkoxylated etheramines, taurates, sarcosinates, polyethylene glycol, polypropylene glycol, EO/PO block polymers and other non-ionic surfactants, particularly the broad class of alkoxylates. It is also expected that the molecules taught will be tolerated by glyphosate tolerant crops.

Several descriptions and illustrations have been presented to enhance understanding of the present invention. One skilled in the art will know that numerous changes and variations are possible without departing from the spirit of the invention. Each of these changes and variations are within the scope of the present invention.