Patent Grant
7541055
Saturated and unsaturated N-alkamide compounds having sweet, salt or umami taste and flavor enhancement quality.
The term Umami, from the Japanese word to describe savory or meaty, is the term used to describe the unique overall fullness, savory or salivatory taste of food. Materials that exhibit this taste quality generally potentate the intensity of glutamate solutions and this is one important characteristic of umami taste. It is increasingly becoming recognized as the fifth sense of taste, the others being sour, sweet, salt and bitter. Compounds traditionally described as possessing this character are monosodium glutamate (MSG), protein hydrolysates, some amino acids and certain nucleotides and phosphates.
MSG is the most widely used material as a ‘taste enhancer’ where it synergizes the perception of ‘savory’ ingredients, but has also been alleged to cause allergic reaction to a proportion of the population.
Among other chemical compounds, several nucleotides have also been described to exhibit the umami effect including Adenosine 5′-(trihydrogen diphosphate), 5′-Cytidylic acid (5′-CMP), 5′-Uridylic acid (5′-UMP), 5′-Adenylic acid (5′-AMP), 5′-Guanylic acid (5′-GMP), 5′-Inosinic acid (5′-IMP) and the di-sodium salts of 5′-Guanylic acid and 5′-Inosinic acid.
Recent literature cites an extensive range of other organic compounds as taste active components of mixtures shown to give the umami taste effect. These include but are not necessarily limited to: organic acids such as succinic acid, lactic acid, saturated straight chain aliphatic acids of six, eight, fourteen, fifteen, sixteen, and seventeen carbon chain lengths, Z4,Z7, Z10,Z13,Z16,Z19-docosahexaenoic acid, Z5,Z8,Z11,Z14,Z17-eicosapentaenoic acid, Z9,Z12,Z16,Z19-octadecadienoic acid, Z9-octadecenoic acid, glutaric acid, adipic acid, suberic acid, and malonic acid. Amino acids having umami effects reported in the literature include glutamic acid, aspartic acid, threonine, alanine, valine, histidine, praline, tyrosine, cystine, methionine, pyroglutamic acid, leucine, lycine, and glycine. Dipeptides possessing umami properties include Val-Glu and Glu-Asp.
Other miscellaneous compounds having umami properties include alpha-amino adipic acid, malic acid, alpha-aminobutyric acid, alpha-aminoisobutyric acid, E2,E4-hexadienal, E2,E4-heptadienal, E2,E4-octadienal, E2,E4-decadienal, Z4-heptenal, E2,Z6-nonadienal, methional, E3,E5-octadien-2-one, 1,6-hexanediamine, tetramethylpyrazine, trimethylpyrazine, cis-6-dodecen-4-olide, glutamate glycoconjugates, fish sauce blended with anchovy paste (U.S. Patent Application 2003/0142090) and a number of naturally occurring amino-acids.
Additionally, a variety of molecules are known by those skilled in the art to provide salt enhancement, these include but are not limited to Adenosine 5′-(trihydrogen diphosphate), 5′-Cytidylic acid (5′-CMP), 5′-Uridylic acid (5′-UMP), 5′-Adenylic acid (5′-AMP), 5′-Guanylic acid (5′-GMP), 5′-Inosinic acid (5′-IMP) and the di-sodium salts of 5′-Guanylic acid and 5′-Inosinic acid, (+)-(S)-Alapyridaine (chemical name N-(1-Carboxyethyl)-6-hydroxymethyl pyridinium-3-ol), succinic acid, cetylpyridium chloride, bretylium tosylate, various polypeptides, mixtures of calcium salts of ascorbic acid, potassium chloride, calcium chloride, magnesium chloride, arginine ammonium chloride, alpha-amino acids and their corresponding hydrogen chloride, ammonium and sodium salts and a number of natural plant extracts. Uses of these materials are described in various U.S. Pat. Nos. 4,997,672; 5,288,510; 6,541,050, U.S. Patent Application 2003/0091721 and Eur. Pat. Appl. 2003/1291342.
Additionally, choline chloride has been shown to enhance salt and increase palatability of sodium chloride reduced systems, Physiol Behav. 1994, 55(6), 1039-46.
In addition to this work, our work has included the identification of new flavor materials described in U.S. Ser. No. 10/919,631 filed on Aug. 17, 2004; U.S. Ser. No. 10/861,751 filed on Jun. 4, 2004; and U.S. Ser. No. 10/783,652 filed Feb. 20, 2004.
Despite these disclosures there is an ongoing need for new flavor ingredients particularly those that exhibit advantageous properties for flavor enhancement or modulation, or more preferably the lowering of MSG and/or salt levels in foodstuffs.
The present invention relates to novel compounds and a process for augmenting or imparting a flavor enhancement effect or modifying the perception of one or more of the five basic taste qualities sweet, sour, salt, bitter and umami, to a foodstuff, chewing gum, medicinal product, toothpaste, alcoholic beverage, aqueous beverage, snack, sauce or soup comprising the step of adding to a foodstuff, chewing gum, medicinal product, toothpaste, alcoholic beverage, aqueous beverage, snack, sauce or soup a flavor enhancement or modification of basic taste quality augmenting, enhancing or imparting quantity and concentration of at least one N-substituted unsaturated alkyl amide defined according to the structures:
The above formulae define novel compounds with the proviso that in structure 1, if R1=H and R2=H, then R3 can not be H or methyl unless R4=R5=H.
As used herein compounds described in structure 2 will be referred to as “cyclopropylic amides”.
A second embodiment relates to novel compounds and a process for augmenting or imparting a flavor enhancement effect or modifying the perception of one or more of the five basic taste qualities sweet, sour, salt, bitter and umami, to a foodstuff, chewing gum, medicinal product, toothpaste, alcoholic beverage, aqueous beverage, snack, sauce or soup comprising the step of adding to a foodstuff, chewing gum, medicinal product, toothpaste, alcoholic beverage, aqueous beverage, snack, sauce or soup a flavor enhancement or modification of basic taste quality augmenting, enhancing or imparting quantity and concentration of at least one N-substituted unsaturated alkyl amide defined according to the structure:
A third embodiment relates to novel compounds and a process for augmenting or imparting a flavor enhancement effect or modifying the perception of one or more of the five basic taste qualities sweet, sour, salt, bitter and umami, to a foodstuff, chewing gum, medicinal product, toothpaste, alcoholic beverage, aqueous beverage, snack, sauce or soup comprising the step of adding to a foodstuff, chewing gum, medicinal product, toothpaste, alcoholic beverage, aqueous beverage, snack, sauce or soup a flavor enhancement or modification of basic taste quality augmenting, enhancing or imparting quantity and concentration of at least one N-substituted unsaturated alkyl amide defined according to the structure:
In addition to the novel compounds and the use of the compounds to enhance the taste of foodstuffs by the incorporation of the above ingredients and others set forth in this specification in foodstuff and other materials.
The formula set forth above describes a general class of novel materials that we have found to enhance the flavor characteristics of food.
In a more preferred embodiment of the invention the amides have the structure set forth in 1 and 2 with wherein
The above compounds of the present invention can be used in accordance with the present method in enhancing the salt and umami effects in foods. The above formulae define novel compounds with the proviso that in structure 1, if R1=H and R2=H, then R3 can not be H or methyl unless R4=R5=H.
In a highly preferred embodiment of the invention the amides have the structure set forth below:
The above compounds of the present invention can be used in accordance with the present method in enhancing the salt and umami effects in foods. The above formulae define novel compounds with the proviso that in structure 1, if R1=H and R2=H, then R3 can not be H or methyl unless R4=R5=H.
As used herein the compounds under structure 1 and formula 1 will be referred to as “alkenylamides”.
In the most preferred embodiment of the invention the amides have the structure set forth below:
The above compounds of the present invention can be used in accordance with the present method in enhancing the salt and umami effects in foods. The above compounds are also novel with the proviso that in Formula II, if R7=H, then R8 can not be H or methyl.
In another preferred embodiment of the invention the amides have the structure set forth below:
In an additional embodiment of the invention a novel compounds and a process for augmenting or imparting a flavor enhancement effect or modifying the perception of one or more of the five basic taste qualities sweet, sour, salt, bitter and umami, to a foodstuff, chewing gum, medicinal product, toothpaste, alcoholic beverage, aqueous beverage, snack, sauce or soup comprising the step of adding to a foodstuff, chewing gum, medicinal product, toothpaste, alcoholic beverage, aqueous beverage, snack, sauce or soup a flavor enhancement or modification of basic taste quality augmenting, enhancing or imparting quantity and concentration of at least one N-substituted unsaturated alkyl amide defined according to the structure:
As used herein the most preferred compounds will be referred to hereinafter as dienalkylamides.
As used throughout the application,
is understood to represent an alkene terminus as depicted in R2, R3, R7 and R8 with an attachment to the alpha carbon of the acid moiety in structures 1, 2, 3, 4, 5 and Formulae I and II set forth in the examples.
Our invention specifically relates to the novel compositions according to the Structure 3 above:
Our invention specifically relates to the novel compositions according to the formula I above:
Referring to Formula II above, the present invention relates to the novel compositions according to the formula II above:
These compounds and uses thereof have been found benficial in augmenting or imparting an olfactory effect taste enhancement or somatosensory effect to a foodstuff, chewing gum, medicinal product, toothpaste, alcoholic beverage, aqueous beverage, snack, sauce or soup particularly providing a (a) umami taste, (b) salt effects, (c) flavor enhancement, and (d) preferred overall flavor profile.
More specifically, examples of the organoleptic properties for the dienalkylamides of our invention are as follows:
Relating to Formula I
Relating to Formula II
Relating to Structure 3
Other novel compounds of the present invention include the following according to Structure 1 above:
Other compounds of the present invention include the following according to Structure 2 above:
Other compounds of the present invention include the following according to Structure 4 above:
Other compounds of the present invention include the following according to Structure 5 above:
The following compounds and Chemical Abstract (CA) names are provided for various compounds of the present invention.
We have surprisingly found the literature has not previously reported dienalkylamides, alkenylamides, or cyclopropylic amides as having or enhancing umami flavor. In addition, closely structurally related compounds such as dienals and unsaturated acids, are not specifically reported to possess umami character when tasted in isolation. In addition the ability to provide an enhanced saltiness for the product without increasing sodium level is not disclosed or suggested by the prior art. The salt enhancing properties of the compounds of the present invention are important because it allows flavorists to provide the desired salty taste profile in foods and beverages without actually having higher salt levels in the food. Therefore the consumer can have both the taste profile that they desire while without having the adverse health effects associated with increased salt levels such as hypertension.
As used herein olfactory effective amount is understood to mean the amount of compound in flavor compositions the individual component will contribute to its particular olfactory characteristics, but the flavor, taste and aroma effect on the overall composition will be the sum of the effects of each of the flavor ingredients. As used herein taste effects include salt, sweet and umami effects. Thus the compounds of the invention can be used to alter the taste characteristics of the flavor composition by modifying the taste reaction contributed by another ingredient in the composition. The amount will vary depending on many factors including other ingredients, their relative amounts and the effect that is desired.
The level of cyclopropylic amides, alkenylamides and dienalkylamides used in products is greater than 50 parts per billion, generally provided at a level of from about 0.01 parts per million to about 50 parts per million in the finished product, more preferably from about 0.1 parts per million to about 20 parts per million by weight, and in preferred embodiments from about 0.5 to about 5 parts per million.
The usage level of cyclopropylic amides, alkenylamides, and dienalkylamides varies depending on the product in which the dienalkylamides are employed. For example, alcoholic beverages the usage level is from about 0.1 to about 5 parts per million, preferably from about 0.5 to about 3 and most preferably from about 1 to about 2 parts per million by weight. Non-alcoholic beverages are flavored at levels of from about 0.05 parts per million to about 5 parts per million, preferably from about 0.1 parts per billion to about 2 parts per million and in highly preferred situations of from about 0.7 to about 1 parts per billion. Other products such as snack foods, candy and gum products can be advantageously flavored using compounds of the present invention at levels described above.
Among the preferred compounds of the present invention are:
The present invention also provides a method for enhancing or modifying the salt flavor of a food through the incorporation of an organoleptically acceptable level of the compounds described herein. The compounds can be used individually or in combination with other salt enhancing compounds of the present invention. In addition, the salt enhancing materials of the present invention can be used in combination with other salt enhancing compositions known in the art, including those materials listed in co-pending applications U.S. Ser. No. 10/919,631 filed on Aug. 17, 2004; U.S. Ser. No. 10/861,751 filed on Jun. 4, 2004; and U.S. Ser. No. 10/783,652 filed Feb. 20, 2004; and also include cetylpyridium chloride, bretylium tosylate, various polypeptides, mixtures of calcium salts of ascorbic acid, sodium chloride and potassium chloride, as described in various U.S. Pat. Nos. 4,997,672; 5,288,510; 6,541,050 and U.S. Patent Application 2003/0091721.
The salt taste enhancing compounds of the present invention may be employed to enhance the perceived salt taste of any salts used in food or beverage products. The preferred salt taste to be enhanced by the compounds of the present invention is that of sodium chloride, primarily because of the discovery that ingestion of large amounts of sodium may have adverse effects on humans and the resultant desirability of reducing salt content while retaining salt taste.
In addition, the compounds of the present invention may also be employed to enhance the perceived salt taste of known salty tasting compounds which may be used as salt substitutes, including potassium chloride and ribonucleotides. Suitable compounds also include cationic amino acids and low molecular weight dipeptides. Specific examples of these compounds are arginine hydrochloride, arginine ammonium chloride, lysine hydrochloride and lysine-ornithine hydrochloride. These compounds exhibit a salty taste but are typically useful only at low concentrations since they exhibit a bitter flavor at higher concentrations. Thus, it is feasible to reduce the sodium chloride content of a food or beverage product by first formulating a food or beverage with less sodium chloride than is necessary to achieve a desired salt taste and then adding to said food or beverage the compounds of the present invention in an amount sufficient to potentiate the salt taste of said salted food or beverage to reach said desired taste. In addition, the sodium chloride content may be further reduced by substituting a salty-tasting cationic amino acid, a low molecular weight dipeptide or mixtures thereof for at least a portion of the salt.
In a preferred embodiment of the present invention we have found the compound of the present invention are materials used in combination with each other or other salt enhancing materials in weight ratios of from about 1:10 to about 10:1, typically from about 1:3 to about 3:1; more preferably from about 1:1 on a weight basis.
In a highly preferred embodiment we have discovered that the compounds of the present invention when used in combination with the compounds disclosed in co-pending application U.S. Ser. No. 10/783,652 filed Feb. 20, 2004. The preferred compounds disclosed in this application include but are not limited to:
The mixtures of the compounds range from about 1:10 to 10:1 weight percent, preferably from about 1:5 to about 5:1 weight percent, most preferably in a 1:2 to a 2:1 weight ratio of the compounds.
Combinations that have been found to provide high levels of salt and umami enhancing effects to products are compounds of the present invention:
The highly preferred weight ratios of these mixtures is from about 2:1 to about 1:2 on a weight basis. Most highly preferred combination is the mixture of Cyclopropanecarboxamide, N-[(2E)-3,7-dimethyl-2,6-octadienyl]- with 2,6-nonadienamide, N-cyclopropyl-, (2E,6Z)- and 2,6-nonadienamide, N-ethyl-, (2E,6Z)- in the ratio about 2:1:1 by weight, with a total use level of 8 ppm. For purpose of illustration that would be a usage level of about 4, 2 and 2 parts per million respectively by weight in a product such as a foodstuff.
The term “foodstuff” as used herein includes both solid and liquid ingestible materials for man or animals, which materials usually do, but need not, have nutritional value. Thus, foodstuffs include food products, such as, meats, gravies, soups, convenience foods, malt, alcoholic and other beverages, milk and dairy products, seafood, including fish, crustaceans, mollusks and the like, candies, vegetables, cereals, soft drinks, snacks, dog and cat foods, other veterinary products and the like.
When the compounds of this invention are used in a flavoring composition, they can be combined with conventional flavoring materials or adjuvants. Such co-ingredients or flavor adjuvants are well known in the art for such use and have been extensively described in the literature. Requirements of such adjuvant materials are: (1) that they be non-reactive with the compounds of our invention; (2) that they be organoleptically compatible with the compounds of our invention whereby the flavor of the ultimate consumable material to which the compounds are added is not detrimentally affected by the use of the adjuvant; and (3) that they be ingestible acceptable and thus nontoxic or otherwise non-deleterious. Apart from these requirements, conventional materials can be used and broadly include other flavor materials, vehicles, stabilizers, thickeners, surface active agents, conditioners and flavor intensifiers.
Such conventional flavoring materials include saturated fatty acids, unsaturated fatty acids and amino acids; alcohols including primary and secondary alcohols, esters, carbonyl compounds including ketones, other than the dienalkylamides of our invention and aldehydes; lactones; other cyclic organic materials including benzene derivatives, acyclic compounds, heterocyclics such as furans, pyridines, pyrazines and the like; sulfur-containing compounds including thiols, sulfides, disulfides and the like; proteins; lipids, carbohydrates; so-called flavor potentiators such as monosodium glutamate; magnesium glutamate, calcium glutamate, guanylates and inosinates; natural flavoring materials such as hydrolyzates, cocoa, vanilla and caramel; essential oils and extracts such as anise oil, clove oil and the like and artificial flavoring materials such as vanillin, ethyl vanillin and the like.
Specific preferred flavor adjuvants include but are not limited to the following: anise oil; ethyl-2-methyl butyrate; vanillin; cis-3-heptenol; cis-3-hexenol; trans-2-heptenal; butyl valerate; 2,3-diethyl pyrazine; methyl cyclo-pentenolone; benzaldehyde; valerian oil; 3,4-dimethoxy-phenol; amyl acetate; amyl cinnamate; γ-butyryl lactone; furfural; trimethylpyrazine; phenyl acetic acid; isovaleraldehyde; ethyl maltol; ethyl vanillin; ethyl valerate; ethyl butyrate; cocoa extract; coffee extract; peppermint oil; spearmint oil; clove oil; anethol; cardamom oil; wintergreen oil; cinnamic aldehyde; ethyl-2-methyl valerate; γ-hexenyl lactone; 2,4-decadienal; 2,4-heptadienal; methyl thiazole alcohol (4-methyl-5-β-hydroxyethyl thiazole); 2-methyl butanethiol; 4-mercapto-2-butanone; 3-mercapto-2-pentanone; 1-mercapto-2-propane; benzaldehyde; furfural; furfuryl alcohol; 2-mercapto propionic acid; alkyl pyrazine; methyl pyrazine; 2-ethyl-3-methylpyrazine; tetramethylpyrazine; polysulfides; dipropyl disulfide; methyl benzyl disulfide; alkyl thiophene; 2,3-dimethyl thiophene; 5-methyl furfural; acetyl furan; 2,4-decadienal; guiacol; phenyl acetaldehyde; β-decalactone; d-limonene; acetoin; amyl acetate; maltol; ethyl butyrate; levulinic acid; piperonal; ethyl acetate; n-octanal; n-pentanal; n-hexanal; diacetyl; monosodium glutamate; mono-potassium glutamate; sulfur-containing amino acids, e.g., cysteine; hydrolyzed vegetable protein; 2-methylfuran-3-thiol; 2-methyldihydrofuran-3-thiol; 2,5-dimethylfuran-3-thiol; hydrolyzed fish protein; tetramethylpyrazine; propylpropenyl disulfide; propylpropenyl trisulfide; diallyl disulfide; diallyl trisulfide; dipropenyl disulfide; dipropenyl trisulfide; 4-methyl-2-[(methylthio)-ethyl]-1,3-dithiolane; 4,5-dimethyl-2-(methylthiomethyl)-1,3-dithiolne; and 4-methyl-2-(methylthiomethyl)-1,3-dithiolane. These and other flavor ingredients are provided in U.S. Pat. Nos. 6,110,520 and 6,333,180.
The cyclopropylic amides, alkenylamides, and dienalkylamides of our invention or compositions incorporating them, as mentioned above, can be combined with one or more vehicles or carriers for adding them to the particular product. Vehicles can be edible or otherwise suitable materials such as ethyl alcohol, propylene glycol, water and the like, as described above. Carriers include materials such as gum arabic, carrageenan, xanthan gum, guar gum and the like.
Cyclopropylic amides, alkenylamides, and dienalkylamides prepared according to our invention can be incorporated with the carriers by conventional means such as spray-drying, extrusion, drum-drying and the like. Such carriers can also include materials for coacervating the dienalkylamides of our invention to provide encapsulated products, as set forth above. When the carrier is an emulsion, the flavoring composition can also contain emulsifiers such as mono- and diglycerides or fatty acids and the like. With these carriers or vehicles, the desired physical form of the compositions can be prepared.
The quantity of cyclopropylic amides, alkenylamides, and dienalkylamides utilized should be sufficient to impart the desired flavor characteristic to the product, but on the other hand, the use of an excessive amount of the compounds is not only wasteful and uneconomical, but in some instances, too large a quantity may unbalance the flavor or other organoleptic properties of the product consumed. The quantity used will vary depending upon the ultimate foodstuff; the amount and type of flavor initially present in the foodstuff; the further process or treatment steps to which the foodstuff will be subjected; regional and other preference factors; the type of storage, if any, to which the product will be subjected; and the preconsumption treatment such as baking, frying and so on, given to the product by the ultimate consumer. Accordingly, the terminology “organoleptically effective amount” and “sufficient amount” is understood in the context of the present invention to be quantitatively adequate to alter the flavor of the foodstuff.
With reference to the novel compounds of our invention, the synthesis is effected by means of the reaction of acid anhydride with amine, added either directly or in solution, according to the general scheme:
where R1, R2, R3, R4, R5 and R6 have the meaning set forth in formula I, and structures 1 and 2 set forth above.
The synthesis of amine follows a literature procedure [The Journal of organic Chemistry 1989, 54, 3292-3303]. The acid anhydride is dissolved in hexanes to which amine is added in 0.9 to 1.0 equivalent at temperatures ranging 0° C. to room temperature, most preferably from 10° C. to 20° C. The resulting solution is aged for about 1-3 hours at room temperature.
The reaction can be quenched with aqueous sodium chloride, hydrogen chloride or sodium hydroxide depending upon the need to remove residual acid or amine. The mixture is extracted into ethereal solvent, washed to neutrality and solvent removed.
The crude product is purified by distillation or recrystallization depending on the physical properties. The reaction occurs in 35-70% mole yield based on amine.
In the case when acid anhydride is not readily available, the synthesis is effected by means of the reaction of acid with ethyl chloroformate in the presence of triethylamine and further reaction of the intermediate with amine, added either directly or in solution, according to the general scheme:
where R1, R2, R3, R4, R5 and R6 have the meaning set forth in formula I, and structures 1 and 2 set forth above.
The acid is dissolved in dichloromethane to which ethyl chloroformate is added in 1.0 to 2.0 equivalents at temperatures ranging from 0° C. to room temperature, most preferably from 10° C. to 20° C. The resulting solution is cooled to −10° C. to −30° C., and triethylamine is added in 1.0 to 2.0 equivalents such that the temperature range is below 0° C. and the mixture aged for 1 hour.
The mixture is filtered, and the filtrate cooled to 0° C. The amine is added in 1.0 to 7.0 equivalents either neat or as a solution in a suitable solvent, the reaction is then aged for about 1-3 hours at room temperature.
The reaction can be quenched with aqueous sodium chloride, hydrogen chloride or sodium hydroxide depending upon the need to remove residual acid or amine. The mixture is extracted into ethereal solvent or dichloromethane, washed to neutrality and solvent removed.
The crude product is purified by distillation or re-crystallization depending on the physical properties.
The reaction occurs in 35-75% mole yield based on acid.
The dienalkylamides of the present invention can be admixed with other flavoring agents and incorporated into foodstuffs and other products using techniques well known to those with ordinary skill in the art. Most commonly the dienalkylamides are simply admixed using the desired ingredients within the proportions stated.
In the preparation of the amides of structure 2 the synthesis of the starting amine can be effected by means of the reaction cyclopropylalkenamines which are formed through standard reduction processes of nitrites using techniques well known to those with ordinary skill in the art. Such nitriles are disclosed in commonly assigned U.S. application Ser. No. 11/154,399 filed Jun. 17, 2005. Specifically, cyclopropanecarbonitriles such as 2-methyl-2-(4-methylpent-3-en-1-yl)-cyclopropanecarbonitrile which may be prepared from the corresponding alkenenitriles, via Corey's cyclopropanation reaction from the corresponding alkenenitriles commercially available from International Flavors & Fragrances Inc., New York, N.Y. The corresponding alkenenitrile is 3,7-dimethyl-octa-2,6-dienenitrile, which is also known under the tradename Citralva.
Those with skill in the art will recognize that the compounds of the present invention have a number of chiral centers, thereby providing several isomers of the claimed compounds. It is intended herein that the compounds described herein include isomeric mixtures of such compounds, as well as those isomers that may be separated using techniques known to those having skill in the art. Suitable techniques include chromatography such as HPLC, and particularly gel chromatography and solid phase microextraction (“SPME”).
The following are provided as specific embodiments of the present invention. Other modifications of this invention will be readily apparent to those skilled in the art, without departing from the scope of this invention. As used herein, in both the specification and following examples, all percentages are understood to be weight percent unless noted to the contrary.
All U.S. Patents and U.S. Patent Applications cited herein are incorporated by reference as if set forth in their entirety. Upon review of the foregoing, numerous adaptations, modifications, and alterations will occur to the reviewer. These will all be, however, within the spirit of the present invention. Accordingly, reference should be made to the appended claims in order to ascertain the true scope of the present invention.
The following reaction sequence was used to prepare the specific compounds described by the NMR data set forth below:
where R1, R2, R3, R4, R5 and R6 have the meaning set forth in formula I, and structures 1 and 2 set forth above.
The acid anhydride was dissolved in hexanes to which amine was added in 0.9 to 1.0 equivalent at temperatures ranging from 0° C. to room temperature, most preferably from 10° C. to 20° C. The resulting solution was aged for about 1-3 hours at room temperature.
The reaction was quenched with aqueous sodium chloride, hydrogen chloride or sodium hydroxide depending upon the need to remove residual acid or amine. The mixture was extracted into ethereal solvent, washed to neutrality and solvent removed.
The crude product was purified by distillation or recrystallization depending on the physical properties.
The amides were synthesized according to the general scheme above with the following specific examples. Equivalents set out are mole equivalents based on starting amine, yields were distilled chemical yields based on starting amine.
Butyric anhydride 1.1eq, 3,7-dimethylocta-2E,6-dienylamine 1 eq, quenched with 10% sodium hydroxide, yield=35%.
1H NMR 0.95 ppm (3H, t, J=7.34 Hz), 1.60 ppm (3H, s), 1.62-1.71 ppm (2H, m), 1.67 ppm (3H, s), 1.68 ppm (3H, s), 2.01 ppm (2H, m), 2.08 ppm (2H, m), 2.15 ppm (2H, m), 3.85 ppm (2H, m), 5.08 ppm (1H, m), 5.19 ppm (1H, m), 5.44 ppm (1H, br. s).
Crotonic anhydride 1.1eq, 3,7-dimethylocta-2E,6-dienylamine 1 eq, quenched with 10% sodium hydroxide, yield=70%.
1H NMR 1.60 ppm (3H, s), 1.68 ppm (6H, m), 1.84-1.91 ppm (3H, m), 1.94-2.09 ppm (4H, m), 3.84 ppm (1H, m), 3.91 ppm (1H, m), 5.08 ppm (1H, m), 5.21 ppm (1H, m), 5.34 ppm (1H, br. s), 5.79 ppm (1H, d, J=15.15 Hz), 6.84 ppm (1H, m).
2-Methylpropionic anhydride 1.1eq, 3,7-dimethylocta-2E,6-dienylamine 1 eq, quenched with 10% sodium hydroxide, yield=58%.
1H NMR 1.17 ppm (d, 6H, J=6.5 Hz), 1.63 ppm (3H, s), 1.69 ppm (3H, s), 1.71 ppm (3H, s), 2.04 ppm (2H, m), 2.08 ppm (2H, m), 2.82 (1H, m), 3.87 ppm (2H, m), 5.10 ppm (1H, m), 5.26 ppm (1H, m), 5.56 ppm (1H, br. s).
Propionic anhydride 1.1eq, 3,7-dimethylocta-2Z,6-dienylamine 1 eq, quenched with 10% sodium hydroxide, yield=76%.
1H NMR 1.15 ppm (m, 3H), 1.60 ppm (s, 3H), 1.69 ppm (s, 3H), 1.72 ppm (s, 3H), 1.98-2.28 ppm (m, 6H), 3.31-3.37 ppm (m, ˜25% of 2H), 3.81-3.83 ppm (m, ˜75% of 2H), 5.09 ppm (s, 1H), 5.20 ppm (m, 1H), 5.59 ppm (br. s, 1H).
Procedure: 1.0 equiv nonyl-2,6-dienylamine, 1.1 equiv acetic anhydride, quenched with 10% sodium hydroxide, 60% yield
1H NMR (500 MHz, CDCl3) 5.65-5.60 (m, 1H), 5.53-5.37 (m, 3H), 5.33-5.28 (m, 1H), 3.82 (t, J=5.7 Hz, 2H), 2.17-2.06 (m, 4H), 2.05-2.02 (m, 2H), 1.99 (s, 3H), 0.96 (t, J=7.53 Hz, 3H).
Procedure: 1.0 equiv nonyl-2,6-dienylamine, 1.1 equiv proponoic anhydride, quenched with 10% sodium hydroxide, 63% yield.
1H NMR (500 MHz, CDCl3) 5.86 (bs, 1H), 5.63-5.30 (m, 4H), 3.81 (s, 2H), 2.23-2.19 (q, J=7.4 Hz, 2H), 2.09-2.01 (m, 6H), 1.16 (t, J=7.5 Hz, 3H), 0.96 (t, J=7.4 Hz, 3H).
Procedure: 1.0 equiv 2-methyl-nonyl-2,6-dienylamine, 1.1 equiv acetic anhydride, quenched with 10% sodium hydroxide, 53% yield
1H NMR (500 MHz, CDCl3) 5.52-5.30 (m, 4H), 3.85 (d, J=5.43 Hz, 0.6H), 3.78 (d, J=5.77 Hz, 1.4H), 2.13-2.01 (m, 6H), 2.00 (s, 0.9H), 1.98 (s, 2.1H), 1.72 (s, 0.9H), 1.62 (s, 2.1H), 0.96 (t, J=7.53 Hz, 3H).
Procedure: 1.0 equiv 3-(2,4-dimethyl)-cyclohex-3-enyl)-allylamine, 1.1 equiv acetic anhydride, quenched with 10% sodium hydroxide, 67% yield
1H NMR (500 MHz, CDCl3) δ 5.75 (bs, 1H), 5.66-5.28 (m, 2H), 5.35-5.25 (d, 0.5H), 5.18 (s, 0.5H), 3.81-3.82 (d, J=5.27 Hz, 2H), 1.98 (s, 3H), 2.05-1.95 (m, 1H), 1.94-1.77 (m, 2H), 1.75-1.57 (m, 2H), 1.63 (s, 3H), 1.54-1.37 (m, 1H), 0.92-0.86 (m, 2.5H), 0.82-0.72 (t, J=7.2 Hz, 0.5H).
Procedure: 1.0 equiv 2-methyl-3-phenyl-allylamine, 1.1 acetic anhydride, quenched with 10% sodium hydroxide, 67% yield
1H NMR (500 MHz, CDCl3) δ 7.32-7.16 (m, 5H), 6.45 (s, 0.8H), 6.38 (s, 0.2H), 5.81 (s, 0.2H), 5.58 (s, 0.8H), 4.06 (d, J=5.61 Hz, 1.6H), 3.96 (d, J=5.97 Hz, 0.4H), 2.04 (s, 0.9H), 1.96 (s, 2.1H), 1.90 (s, 2.3H), 1.86 (s, 0.7H).
Isobutyric anhydride 1.1eq, 3,7-dimethylocta-2Z,6-dienylamine 1 eq, quenched with 10% sodium hydroxide, yield=80%.
1H NMR 1.15 ppm (d, 6H, J=6.8 Hz, of d, J=2.4 Hz), 1.60-1.73 ppm (m, 9H), 1.98-2.24 ppm (m, 4H), 2.27-2.35 ppm (m, 1H), 3.83 ppm (m, 2H), 5.09 ppm (m, 1H), 5.16-5.28 ppm (m, 1H), 5.46 ppm (br. s, 1H).
The following reaction sequence was used to prepare the specific compounds described by the NMR data set forth below:
The acid was dissolved in dichloromethane to which ethyl chloroformate was added in 1.0 to 2.0 equivalents at temperatures ranging from 0° C. to room temperature, most preferably from 10° C. to 20° C. The resulting solution was cooled to −10° C. to −30° C., and triethylamine is added in 1.0 to 2.0 equivalents such that the temperature range was below 0° C. and the mixture aged for 1 hour.
The mixture was filtered, and the filtrate cooled to 0° C. The amine was added in 1.0 to 7.0 equivalents either neat or as a solution in THF and the reaction was aged for about 1-3 hours at room temperature.
The reaction was quenched with aqueous sodium chloride, hydrogen chloride or sodium hydroxide depending upon the need to remove residual acid or amine. The mixture was extracted into ethereal solvent or dichloromethane, washed to neutrality and solvent removed.
The crude product was purified by distillation or recrystallization depending on the physical properties.
The amides were synthesized according to the general scheme above with the following specific examples. Equivalents set out are mole equivalents based on starting acid, yields were distilled chemical yields based on starting acid.
In some of the following examples acid chloride is used in place of carboxylic acid and ethyl chloroformate.
2E,6Z-Nonadienoic acid 1.0eq, ethyl chloroformate 1.5eq, triethylamine 1.5eq, 3,7-dimethylocta-2E,6-dienylamine 1.6eq, quenched with 10% sodium chloride solution, yield=50%.
1H NMR 0.95 ppm(t, 3H, J=7.53 Hz), 1.60 ppm (s, 3H), 1.68 ppm (s, 6H), 1.96-2.13 ppm (m, 6H), 2.17-2.22 ppm (m, 4H), 3.91 ppm (t, 2H, J=6.07 Hz), 5.06-5.09 ppm (m, 1H), 5.22 ppm (t, 1H, J=6.98 Hz), 5.28-5.33 ppm (m, 1H), 5.37-5.43 ppm (m, 1H), 5.58 ppm (br. s, 1H), 5.79 ppm (d, 1H, J=15.33 Hz), 6.82 ppm (d, 1H, J=15.25 Hz, of t, J=6.59 Hz).
Trimethylacetic acid 1.0 eq, ethyl chloroformate 1.5eq, triethylamine 1.5eq, 3,7-dimethylocta-2E,6-dienylamine 1.6eq, quenched with 10% sodium chloride solution, yield=41%.
1H NMR 1.20 ppm (2s, 9H), 1.60 ppm (s, 3H), 1.67 ppm (s, 3H), 1.68 ppm (s, 3H), 1.98-2.10 ppm (m, 4H), 3.82-3.84 ppm (m, 2H), 5.07-5.09 ppm (m, 1H), 5.17-5.20 ppm (m, 1H), 5.53 ppm (br. s, 1H).
3,3-Dimethylacrylic acid 1.0eq, ethyl chloroformate 1.5eq, triethylamine 1.5eq, 3,7-dimethylocta-2E,6-dienylamine 1.6eq, quenched with 10% sodium chloride solution, yield=16%.
1H NMR 1.60 ppm (s, 3H), 1.67 ppm (s, 3H), 1.68 ppm (s, 3H), 1.83 ppm (s, 3H), 1.95-2.02 ppm (m, 2H), 2.06-2.13 ppm (m, 2H), 2.15 ppm (s, 3H), 3.85-3.89 ppm (m, 2H), 5.07-5.09 ppm (m, 1H), 5.20-5.22 ppm (m, 1H), 5.42 ppm (br. s, 1H), 5.56 ppm (s, 1H).
2-Methyl-2E-butenoic acid 1.0eq, ethyl chloroformate 1.5eq, triethylamine 1.5eq, 3,7-dimethylocta-2E,6-dienylamine 1.6eq, quenched with 10% sodium chloride solution, yield=31%.
1H NMR 1.60 ppm (s, 3H), 1.68-1.71 ppm (2s, 6H), 1.74-1.75 ppm (2s, 3H), 1.84 ppm (s, 3H), 1.96-2.03 ppm (m, 2H), 2.07-2.15 ppm (m, 2H), 3.89-3.91 ppm (m, 2H), 5.07-5.09 ppm (m, 1H), 5.21-5.24 ppm (m, 1H), 5.60 ppm (br. s, 1H), 6.40-6.42 ppm (m, 1H).
2-Methylbutanoic acid 1.0eq, ethyl chloroformate 1.5eq, triethylamine 1.5eq, 3,7-dimethylocta-2E,6-dienylamine 1.6eq, quenched with 10% sodium chloride solution, yield=46%.
1H NMR 0.89-0.92 ppm (m, 3H), 1.12-1.17 ppm (m, 3H), 1.39-1.45 ppm (m, 1H), 1.51-1.80 ppm (m, 1H), 1.60 ppm (s, 3H), 1.67 ppm (s, 3H), 1.68 ppm (s, 3H), 1.97-2.17 ppm (m, 5H), 3.86 ppm (s, 2H), 5.08 ppm (s, 1H), 5.18-5.21 ppm (m, 1H), 5.30-5.67 ppm (br. s, 1H).
Cyclopropanecarboxic acid 1.0eq, ethyl chloroformate 1.5eq, triethylamine 1.5eq, 3,7-dimethylocta-2Z,6-dienylamine 1.6eq, quenched with 10% sodium chloride solution, yield=56%.
1H NMR 0.70-0.71 ppm (m, 2H), 0.94-0.96 ppm (m, 2H), 1.30-1.34 ppm (m, 1H), 1.61-1.73 ppm (m, 9H), 1.98-2.28 ppm (m, 4H), 3.83-3.88 ppm (m, 2H), 5.10 ppm (m, 1H), 5.20-5.24 ppm (m, 1H), 5.72 ppm (br. s, 1H).
Cyclopropanecarboxic acid 1.0eq, ethyl chloroformate 1.5eq, triethylamine 1.5eq, 3-methyl-2-butenylamine 1.6eq, quenched with 10% sodium chloride solution, yield=17%.
1H NMR 0.69-0.73 ppm (m, 2H), 0.95-0.98 ppm (m, 2H), 1.28-1.33 ppm (m, 1H), 1.68 ppm (s, 3H), 1.73 ppm (s, 3H), 3.85 ppm (t, 2H, J=6.1 Hz), 5.21 ppm (t, 1H, J=7.1 Hz), 5.50 ppm (br. s, 1H).
Procedure: 1.0 equiv dodecyl-2,6-dienylamine, 1.1 equiv cyclopropanecarbonyl chloride, 1.5 equiv triethylamine, quenched with water, 61% yield.
1H NMR (500 MHz, CDCl3) 5.65-5.61 (m, 2H), 5.50-5.46 (m, 1H), 5.40-5.33 (m, 2H), 3.84 (m, 2H), 2.11-2.07 (m, 4H), 2.03-1.99 (m, 2H), 1.35-1.26 (m, 7H), 0.99-0.96 (m, 2H), 0.89 (t, J=7.18 Hz, 3H), 0.74-0.71 (m, 2H).
Procedure: 1.0 equiv 3-(4-methyl-cyclohex-3-enyl)-but-2-enylamine, 1.1 equiv acetyl chloride, 1.5 equiv triethylamine, quenched with water, 42% yield
1H NMR (500 MHz, CDCl3) δ 6.13 (bs, 1H), 5.38 (s, 1H), 5.23-5.16 (m, 1H), 3.87-3.79 (m, 2H), 2.16-2.02 (m, 2H), 1.97 (s, 3H), 2.01-1.95 (m, 1H), 1.92-1.77 (m, 1H), 1.74-1.68 (m, 1H), 1.66-1.60 (m, 6H), 1.59-1.25 (m, 2H).
Procedure: 1.0 equiv nonyl-2,6-dienylamine, 1.1 equiv cyclopropanecarbonyl chloride, 1.5 equiv triethylamine, quenched with water, 63% yield.
1H NMR (500 MHz, CDCl3) 5.80-5.28 (m, 5H), 3.90 (d, J=6.06 Hz, 0.33H), 3.84 (t, J=5.65 Hz, 1.67H), 2.17-1.98 (m, 6H), 1.34-1.29 (m, 1H), 0.96 (t, J=7.5 Hz, 3H), 1.02-0.93 (m, 2.33H), 0.75-0.71 (m, 1.67H).
Procedure: 1.0 equiv 2-methyl-nonyl-2,6-dienylamine, 1.1 equiv cyclopropanecarbonyl chloride, 1.5 equiv triethylamine, quenched with water, 58% yield.
1H NMR (500 MHz, CDCl3) 5.52-5.30 (m, 4H), 3.91-3.80 (m, 2H), 2.13-1.95 (m, 6H), 1.73 (s, 1H), 1.63 (s, 2H), 1.38-1.28 (m, 1H), 0.96 (t, J=7.5 Hz, 3H), 1.00-0.94 (m, 1.5H), 0.93-0.84 (m, 1H), 0.75-0.71 (m, 1.5H).
Procedure: 1.0 equiv 3-(2,4-dimethyl)-cyclohex-3-enyl)-allylamine, 1.1 equiv cyclopropanecarbonyl chloride, 1.5 equiv triethylamine, quenched with water, 65% yield.
1H NMR (500 MHz, CDCl3) δ 5.75 (bs, 1H), 5.66-5.44 (m, 2H), 5.35-5.28 (d, 0.5H), 5.19 (s, 0.5H), 3.90-3.79 (m, 2H), 2.05-1.81 (m, 3H), 1.65 (d, 3H), 1.72-1.57 (m, 1H), 1.57-1.41 (m, 1H), 1.40-1.18 (m, 2H), 0.97-0.95 (m, 2H), 0.92 (d, J=6.1 Hz, 1.8H), 0.89 (d, J=6.5 Hz, 1.2H), 0.73-0.70 (m, 2H).
Procedure: 1.0 equiv 2-methyl-3-phenyl-allylamine, 1.1 equiv cyclopropanecarbonyl chloride, 1.5 equiv triethylamine, quenched with water, 69% yield
1H NMR (500 MHz, CDCl3) δ 7.33 (dd, J=8.57, 7.33. Hz, 2H), 7.25 (d, J=8.57 Hz, 2H), 7.21 (t, J=7.33 Hz, 1H), 6.40 (s, 1H), 5.80 (bs, 1H), 4.00 (d, J=5.97 Hz, 2H), 1.87 (s, 3H), 1.41-1.38 (m, 1H), 1.02-1.00 (m, 2H), 0.78-0.75 (m, 2H).
Cyclopropanecarboxylic acid 1 eq, ethyl chloroformate 1.5eq, triethylamine 1.5eq, 3,7-dimethylocta-2E,6-dienylamine 1.6eq, quenched with 10% sodium chloride solution, yield=36%.
0.71 ppm (2H, m), 0.96 ppm (2H, m), 1.33 ppm (1H, m), 1.60 ppm (3H, s), 1.67 ppm (3H, s), 1.69 ppm (3H, s), 2.01 ppm (2H, m), 2.08 ppm (2H, m), 3.87 ppm (2H, m), 5.08 ppm (1H, m), 5.21 ppm (1H, m), 5.61 ppm (1H, br. s).
Taste tests were conducted with various molecules. The following molecule (A) IS disclosed and claimed in this specification. Molecules (B) and (J) are disclosed and claimed as flavor materials in co-pending application U.S. Ser. No. 10/783,652 filed Feb. 20, 2004. These materials were used in the following taste examples.
A trained consumer panel of about 16 flavorists, evaluated the above molecules in tasting solutions and were asked to rate the perception of salt and umami for each taste solution. The taste solutions presented to the panelists contained 0.3% by weight NaCl, 0.1% MSG and 0.015% Ribotides, a commercially available blend of disodium guanylate and disodium inosinate. The above molecules were added to the tasting solution at 1 and 4 parts per million.
The taste panel found the molecules of the invention increased the salt and umami perception in excess of 40%. This increase in the salty and umami taste of the base was higher than the increase seen when KCl was added to the base at levels of 0.12%, or when the total amount of salt, MSG and ribotides in the base were increased by 40%.
A trained panel of flavorists and scientists were given a series of paired taste samples containing by weight 0.3% NaCl, 0.1% MSG and 0.015% ribotides. For each member of the panel two samples were prepared. One sample given was the unaltered taste solution, the second sample was the sample one with the addition of one part per million of the above molecules. The panelists found the samples containing the molecules to have higher salt and umami character; the increase in salty and umami perception was increased by up to about 20%.
An expert panel of flavorists and food technologists were asked to blindly evaluate a series of reduced sodium beef broths containing between one and four ppm of the molecules of this invention set forth above. The panel found the broths to be significantly higher in saltiness and umami mouthfeel.
A commercially available rice side dish was prepared with and without the addition of compounds from this invention. The above described molecules were added at 3 ppm to the prepared rice mix. The rice mix was then prepared on the stove top according to the directions on the package. An expert panel of flavorists and food technologists were asked to rate the saltiness or the samples. The panel found that the rice samples with the addition of the molecules was significantly saltier than the unflavored reference.
The molecules of this invention were added to a commercially available noodle side dish at 2 ppm. A panel of flavorists and food technologists was presented the flavored and unflavored samples blind and asked to comment on the taste differences. The samples containing the molecules were uniformly rated as saltier than the unflavored samples.
The panel of flavorists and food technologists used in earlier examples were asked to evaluate a series of reduced sodium chicken broth versus a full sodium chicken broth. In this degree of difference testing, the panel was able to find a significant difference in the taste of chicken broth containing 10% less salt. The panel found the difference in the taste of the low salt sample to be pronounced when the salt was reduced by 15%.
Samples of lower salt chicken broth containing 800 parts per billion of the molecules of the invention provided above were given to this panel for evaluation. The panel could not perceive the difference between the full salt chicken broth and the chicken broth with 15% less salt containing the molecules set forth above. A sample of broth containing molecules of this invention with a 20% reduction in salt was not perceived as significantly different from the full salt broth.
The following reaction sequences were used to prepare the specific compounds described by the NMR data set forth below:
To a reaction flask under nitrogen, NaH (2.0 g, 50 mmol) and 100 mL of toluene were charged. The reaction was heated to 80° C., and amide (10 g, 48 mmol) was fed over 25 minutes. The mixture was aged for 1 hour, then dimethylsulfide (DMS) (4.1 g, 33 mmol) was fed in to the reaction over 15 minutes. The reaction was allowed to age for 4 hours, and was then quenched with 85 g of 25% (wt/wt) NaOH solution. The reaction was aged at 80° C. for 1 hour, then the layers were separated and the organic layer was washed twice with warm water. The solvent was removed under reduced pressure. The product was purified by silica gel chromatography eluting with (0-50% EtOAc/hexanes) to give 6.3 g of product, 60% yield.
1H NMR (500 MHz, CDCl3) 5.59 (m, 1H), 5.50-5.36 (m, 2H), 5.30 (m, 1H), 4.01 (s, 1H), 3.94 (s, 1H), 3.07 (s, 1.5H), 2.91 (s, 1.5H), 2.12 (m, 4H), 2.03 (m, 2H), 1.71 (m, 1H), 0.96 (m, 2H), 0.96 (t, J=7.53 Hz, 3H), 0.73 (m, 2H).
To a reaction flask under nitrogen, NaH (1.2 g, 29 mmol) and 50 mL of toluene were charged. The reaction was heated to 80° C., and amide (6.0 g, 27 mmol) dissolved in 25 mL of toluene was fed in over 30 minutes. The mixture was aged for 1 hour, then dimethylsulfide (2.4 g, 19 mmol) was fed in to the reaction over 5 minutes. The reaction was allowed to age for 4 hours, and was then quenched with 61 g of 25% (wt/wt) NaOH solution. The reaction was aged at 80° C. for 1 hour, then the layers were separated and the organic layer was washed twice with warm water. The solvent was removed under reduced pressure. The product was purified by kugelrohr distillation to give 4.2 g of product, 66% yield.
1H NMR (500 MHz, CDCl3) 5.21-5.11 (m, 1H), 5.08-5.07 (m, 1H), 4.08-4.02 (m, 1H), 3.88-3.85 (m, 1H), 3.07 (s, 1.5H), 2.91 (s, 1.5H), 2.10-2.00 (m, 4H), 1.73-1.68(m, 7H), 1.60 (m, 3H), 0.98-0.96 (m, 2H), 0.74-0.70 (m, 2H).
Cyclopropanecarboxamide, N-[3,7-dimethyl-octa-2,6-dienyl]-N-ethyl-(2E)
To a reaction flask under nitrogen, NaH (1.2 g, 29 mmol) and 50 mL of toluene were charged. The reaction was heated to 80° C., and amide (6.0 g, 27 mmol) dissolved in 25 mL of toluene was fed in over 30 minutes. The mixture was aged for 1 hour, then diethylsulfide (DES) (3.0 g, 19 mmol) was fed in to the reaction over 5 minutes. The reaction was allowed to age for 4-hours, and was then quenched with 61 g of 25% (wt/wt) NaOH solution. The reaction was aged at 80° C. for 1 hour, then the layers were separated and the organic layer was washed twice with warm water. The solvent was removed under reduced pressure. The product was purified by silica gel chromatography eluting with (0-50% EtOAc/hexanes) to give 3.6 g of product, 57% yield.
1H NMR (500 MHz, CDCl3 5.21-5.11 (m, 1H), 5.08-5.07 (m, 1H), 4.08-4.02 (m, 1H), 3.88-3.85 (m, 1H), 3.53-3.36 (m, 2H), 2.10-2.00 (m, 4H), 1.73-1.68(m, 7H), 1.60 (m, 3H), 1.28-1.21 (m, 1.5H), 1.18-1.09 (m, 1.5H), 0.98-0.96 (m, 2H), 0.74-0.70 (m, 2H).
To a reaction flask under nitrogen, NaH (2.3 g, 56 mmol) and 100 mL of THF were charged. The reaction was heated to 50° C., and amide (10.0 g, 50 mmol) was fed in over 45 minutes. The mixture was aged for 1 hour, then bromomethylcyclopropane (11 g, 80 mmol) was fed in to the reaction over 15 minutes. The reaction was allowed to age for 4 hours, and was then quenched with 75 mL of water. The layers were separated and the organic lasyer was washed with saturated NaHCO3 solution, water, and brine. The solvent was removed under reduced pressure. The product was purified by silica gel chromatography eluting with (0-50% EtOAc/hexanes) to give 6.2 g of product, 48% yield.
1H NMR (500 MHz, CDCl3 5.58-5.52 (m, 1H), 5.42-5.33 (m, 2H), 5.30-5.27 (m, 1H), 4.05 (d, J=6.12 Hz, 0.8H), 3.92 (d, J=4.97 Hz, 1.2H), 3.24 (d, J=6.8 Hz, 1.2H), 3.13 (d, J=6.5 Hz, 0.8H), 2.38 (q, J=7.4 Hz, 0.8H), 2.33 (q, J=7.4 Hz, 1.2H), 2.10 (bs, 4H), 2.02 (m, 2H), 1.16 (t, J=7.4 Hz, 1.2H), 1.14 (t, J=7.4 Hz, 1.8H), 0.95 (t, J=7.5 Hz, 3H), 1.0-0.93 (m, 0.4H), 0.93-0.84 (m, 0.6H), 0.57-0.53 (m, 0.8H), 0.49-0.45 (m, 1.2H), 0.23-0.18 (m, 2H).
Standard reduction processes of nitriles as described above and disclosed in commonly assigned U.S. application Ser. No. 11/154,399 filed Jun. 17, 2005 were used to prepare specific amine precursors of compounds described by the NMR data set forth below:
To a reaction flask under nitrogen, 1-[2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropyl]methanamine (10.0 g, 0.06 mol), triethylamine (10.4 mL, 0.07 mol), and 75 ml of anhydrous methylene chloride. The reaction was cooled to −5° C. and cyclopropane carboxylic acid chloride (6.9 g, 0.066 mol) was feed in dropwise. Once the feed was complete the reaction mixture was aged for 3 hours at room temperature before quenching with 75 mL of water. The organic was extracted and washed with brine. Kugelrohr distillation afforded 8.1 g of product, 57% yield.
1H NMR (500 MHz, CDCl3) δ: 0.08-0.16 (m, 1H), 0.46-0.51 (m, 1H), 0.77-0.98 (m, 5H), 1.05-1.09 (2s, 3H), 1.11-1.18 (m, 1H), 1.26-1.40 (m, 2H), 1.61-1.74 (m, 6H), 2.01-2.17 (m, 2H), 3.33 (br. s, 2H), 5.10 (m, 1H), 5.58 (br. s, 1H).
Acetyl Chloride 1.1 eq, 1-[2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropyl]methanamine 1.0 eq, triethylamine 1.2 eq, quenched with water yield 65% yield.
1H NMR (500 MHz, CDCl3) δ: 0.09-0.13 (m, 1H), 0.42-0.51 (m, 1H), 0.72-0.79 (m, 1H), 1.05-1.07 (2s, 3H), 1.09 & 1.43 (m, 3H), 1.62 (s, 3H), 1.69 (s, 3H), 1.98 (s, 3H), 2.01-2.09 (m, 2H), 3.11-3.36 (m, 2H), 5.08-5.11 (m, 1H), 5.41 (br. s., 1H).
Propionyl chloride 1.1 eq, 1-[2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropyl]methanamine 1.0 eq, triethylamine 1.2 eq, quenched with water yield 62% yield.
1H NMR (500 MHz, CDCl3) δ: 0.09-0.14 (m, 1H), 0.45-0.51 (m, 1H), 0.73-0.79 (m, 1H), 1.05-1.07 (2s, 3H), 1.09-1.14 & 1.31-1.39 (m, 3H), 1.17 (t, J=7.55 Hz, 3H), 1.61 (s, 3H), 1.68 (s, 3H), 2.04-2.09 (m, 2H), 2.20 (q, J=7.57 Hz, 2H), 3.11-3.86 (m, 2H), 5.08-5.12 (m, 1H), 5.38 (m, 1H).
The reaction sequence according to Example 2 was used to prepare specific compounds described by the NMR data set forth below:
Isobutyric anhydride 1.1 eq, 1-[2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropyl]methanamine 1.0 eq, triethylamine 1.2 eq, quenched with water yield 70% yield.
1H NMR (500 MHz, CDCl3) δ: 0.10-0.14 (m, 1H), 0.45-0.51 (m, 1H), 0.73-0.79 (m, 1H), 1.05-1.07 (2s, 3H), 1.09-1.13 & 1.31-1.39 (m, 3H), 1.16 (d, J=6.89 Hz, 6H), 1.61 (s, 3H), 1.68 (s, 3H), 2.01-2.10 (m, 2H), 2.34 (septet, J=6.89 Hz, 1H), 3.09-3.86 (m, 2H), 5.08-5.12 (m, 1H), 5.39 (br. s., 1H).
Crotonic anhydride 1.1 eq, 1-[2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropyl]methanamine 1.0 eq, triethylamine 1.2 eq, quenched with water yield 61% yield.
1H NMR (500 MHz, CDCl3) δ: 0.10-0.15 (m, 1H), 0.45-0.51 (m, 1H), 0.75-0.82 (m, 1H), 1.05-1.08 (2s, 3H), 1.10-1.15 (m, 1H), 1.3-1.39 (m, 1H), 1.61 (s, 3H), 1.68 (s, 3H), 1.85 (d, J=6.8 Hz, 3H), 2.02-2.09 (m, 2H), 3.17-3.44 (m, 2H), 5.08-5.12 (m, 1H), 5.36 (br. s, 1H), 5.79 (d, J=15.2 Hz, 1H), 6.83 (dq, J=15.1, 6.9 Hz, 1H).
The reaction sequence according to Example 2, where R1-R7 have the same meaning as set forth in structure 5, was used to prepare specific compounds described by the NMR data set forth below:
2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropanecarboxylic acid (20.0 g, 0.11 mol) in 150 mL of ethyl acetate and ethylchloroformate (17.9 g, 0.165 mol) were charged to a reaction flask. The reaction mixture was then cooled to 0° C. Triethylamine (23.8 g, 0.165 mol) was slowly added while maintaining the reaction temperature at 0° C. Once the feed was complete the reaction mixture was aged for 2 hours. Next, cyclopropylamine (18.8 g, 0.33 mol) was slowly added over 1 hour. Once the feed was complete the reaction mixture was allowed to warm to room temperature and aged for 2 hours. The reaction mixture was then quenched with 200 mL of water, extracted with diethyl ether and washed with brine. Kugelrohr distillation afforded 15.1 g of the product, 62% yield.
1H NMR (500 MHz, CDCl3) δ: 0.44-0.90 (m, 6H), 1.06 (t, 1H, J=4.77 Hz) 1.1 & 1.14 (2s, 3H), 1.16-1.43 (m, 2H), 1.60-1.70 (m, 6H), 2.01-2.13 (m, 2H), 2.68-2.75 (m, 1H), 5.09 (br. s, 1H), 5.45-5.64 (m, 1H).
Dimethylamine 3.0 eq, 2-[(3Z)-hex-3-en-1-yl]cyclopropanecarboxylic acid 1.0 eq, ethylchloroformate 2.0 eq, triethylamine 2.0 eq, quenched with saturated sodium chloride solution, 55% yield.
1H NMR (500 MHz, CDCl3) δ: 0.61 (m, 1H), 0.95 (t, J=7.52 Hz, 3H), 0.96 (m, 1H), 1.17 (m, 1H), 1.37 (m, 2H), 1.49 (m, 2H), 2.04 (p, J=7.16 Hz, 2H), 2.14 (q, J=6.69 Hz, 2H), 2.95 (s, 3H), 3.15 (s, 3H), 5.30-5.49 (m, 2H).
Ethylamine 3.0 eq, 2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropanecarboxylic acid 1.0 eq, ethylchloroformate 2.0 eq, triethylamine 2.0 eq was quenched with saturated sodium chloride solution to give a 63% yield.
1H NMR (500 MHz, CDCl3) δ: 0.70 (m, 1H), 1.12-1.70 (m, 16 H), 1.92-2.20 (m, 2H), 3.30 (m, 2H), 5.08-5.11 (m, 1H), 5.49-5.52 (m, 1H).
Isobutylamine 3.0 eq, 2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropanecarboxylic acid 1.0 eq, ethylchloroformate 2.0 eq, triethylamine 2.0 eq was quenched with saturated sodium chloride solution to give a 71% yield.
1H NMR (500 MHz, CDCl3) δ: 0.71 (br. s. 1H), 0.92 (d, J=6.43 Hz, 6H), 1.06 (m, 1H), 1.121.14 (2s, 3H), 0.19-1.26 (m, 2H), 1.39-1.44 (m, 1H), 1,61 (2s, 3H), 1.69 (2s, 3H), 1.74-1.82 (m, 1H), 1.93-2.13 (m, 2H), 3.11 (br. s, 2H), 5.09-5.12 (m, 1H), 5.54 (br. s, 1H).
Methylamine 3.0 eq, 2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropanecarboxylic acid 1.0 eq, ethylchloroformate 2.0 eq, triethylamine 2.0 eq was quenched with saturated sodium chloride solution to 51% yield.
1H NMR (500 MHz, CDCl3) δ: 0.70-0.72 & 1.05-1.07 (m, 1H), 1.11-1.15 (2s, 3H), 1.17-1.26 & 1.27-1.43 (m, 2H), 1.59-1.70 (m, 7H), 1.906-2.13 (m, 2H), 2.82 (s, 3H), 5.06-5.11 (m, 1H), 5.25-5.32 & 5.49 (m, 1H).
Allylamine 3.0 eq, 2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropanecarboxylic acid 1.0 eq, ethylchloroformate 2.0 eq, triethylamine 2.0 eq was quench with saturated sodium chloride solution to produce a 72% yield.
1H NMR (500 MHz, CDCl3) δ: 0.71-0.74 (m, 1H), 0.84-0.90 (m, ˜38% of 1H) 1.08(t, ˜62% of 1H, J=4.87 Hz), 1.12-1.15 (2s, 3H), 1.21-1.28 (m, 2H), 1.41-1.50 (m, 1H), 1.55-1.69 (m, 6H), 1.95-2.14 (m, 2H), 3.88-3.93 (m, 2H), 5.08-5.14 (m, 2H), 5.17-5.22 (m, 1H), 5.53-5.66 (m, 1H), 5.81-5.92 (m, 1H).
Isopropyl amine 3.0 eq, 2-methyl-2-(4-methylpent-3-en-1-yl)cyclopropanecarboxylic acid 1.0 eq, ethylchloroformate 2.0 eq, triethylamine 2.0 eq was quenched with saturated sodium chloride solution to provide a 68% yield.
1H NMR (500 MHz, CDCl3) δ: 0.65-0.69 & 1.03-1.04 (m, 1H), 1.11-1.30 (n, 12H), 1.39-1.46 & 1.46-1.51 (m, 1H), 1.59-1.71 (m, 6 H), 1.94-2.10 (m, 2H), 4.06-4.11 (m, 1H), 5.08-5.12 (m, 1H), 5.29-5.33 (m, 1H).
A consumer panel trained in basic taste for ranking of intensity and quality of the basic taste attribute were asked to compare Umami strength of solutions of MSG, Ribotides, a commercially available blend of disodium guanylate and disodium inosinate and molecules of this invention.
A 440 mg Sodium broth base was used as the reference and testing was done according to the following protocol.
Objectives:
Procedures:
The results showed that addition of 2 ppm of the preferred molecules of the invention added about the same intensity of additional Umami character as addition of an additional 0.5% salt, or 0.65% MSG or 0.08% ribotides.
This application is a continuation-in-part of U.S. Ser. No. 10/939,096, filed on Sep. 10, 2004 now U.S. Pat. No. 7,427,421 the contents hereby incorporated by reference as if set forth in its entirety.
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| Number | Date | Country | |
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| Child | 11178179 | US |
