CN101426381A - Comestible compositions comprising high potency savory flavorants, and processes for producing them - Google Patents
Comestible compositions comprising high potency savory flavorants, and processes for producing them Download PDFInfo
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- CN101426381A CN101426381A CNA200780014410XA CN200780014410A CN101426381A CN 101426381 A CN101426381 A CN 101426381A CN A200780014410X A CNA200780014410X A CN A200780014410XA CN 200780014410 A CN200780014410 A CN 200780014410A CN 101426381 A CN101426381 A CN 101426381A
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Abstract
The present invention relates to the use of certain high potency savory (''umami'') taste modifiers, as savory flavoring agents and/or enhancers of monosodium glutamate, for the preparation of foods, beverages, and other comestible compositions, and to processes for preparing food flavorant compositions for use in the preparation of comestible food and drink.
Description
Related application
The application requires to submit on April 21st, 2006, sequence number is 60/793,844 U.S. Provisional Patent Application and on September 27th, 2006 submit to, sequence number is 60/847, the priority of 632 U.S. Provisional Patent Application, the full content that these applications disclose is hereby incorporated by.
Technical field
The invention that this paper discloses relate to some efficient delicate flavour (high potency savory) (" umami " is the meaning of Japanese " delicate flavour ") taste conditioning agent (taste modifier) as tasty agents (savory flavoringagent) and/or sodium glutamate reinforcing agent (enhancer) purposes in preparation food, beverage and other edible composition, and relate to the method for preparing food seasoning concentrate composition (food flavorant concentratecompositon), described food seasoning concentrate composition is used to prepare Food ﹠ Drink.The invention still further relates to the method for some delicate flavour tastant compound (savory tastant compound) of preparation this paper disclosure.
Background of invention
For centuries, people are added in the edible Food ﹠ Drink various natural and non-natural compositions and/or compound to improve their taste.Although just knew " taste (taste) " that several fundamental types are only arranged for a long time, but biological basis and biochemical basis to the taste perception are also known little about it, and flavor improving agent that has been found that and taste conditioning agent major part are by simple experiment and discovery by accident.
For example, " delicate flavour " (" savory " or " umami ") of bringing for sodium glutamate (" MSG ") of one of 5 kinds of known primary tastes.Usually that will synthesize or natural MSG is added in the food, adds concentration and is generally about 0.05 to about 0.5wt%.Perhaps, MSG is present in some food additives, and can add by the form of some food additives, described food additives for example are that these additives are added in the edible Food ﹠ Drink with about concentration of 0.1 to about 2wt% usually from dissolubility yeast extract (" AYE ") or hydrolyzed vegetable protein (" HVP ").Yet MSG has notified in some people's body and has produced side reaction, and MSG contain significant quantity do not wish the sodium that contains, but at present aspect the artificial substituent who seeks MSG almost without any progress.
More known naturally occurring materials can strengthen or improve the effect of (reinforcement) MSG as tasty agents, thereby reduce the amount of MSG in given seasoning purposes.For example, naturally occurring nucleotide compound inosine monophosphate (IMP) and the known delicate flavour to MSG of guanosine monophosphate (GMP) have reinforcing agent (" promoter ") effect.IMP and GMP also can be present in AYE or the HVP food additives, but from natural material IMP is separated with GMP and purifying or to they synthesize be difficulty and also cost high, so the practical application of these two kinds of materials is restricted.Thereby can replace the MSG tasty agents maybe can improve the high efficiency compound that any existing MSG effect reduces MSG consumption in the food compositions and can have very high value.
In recent years, bioengineering field is obtained remarkable break-throughs generally, and people understand intensification to the biological basis and the biochemical basis of taste perception.For example, people have identified the taste receptor protein (taste receptor proteins) of mammiferous participation taste perception recently.Particularly identify two kinds of different g protein coupled receptor families, T2R family and T1R family believe to participate in taste sense by these two kinds of albumen (referring to as Nelson etc., Cell (2001) 106 (3): 381-390; Adler etc., Cell (2000) 100 (6): 693-702; Chandrashekar etc., Cell (2000) 100:703-711; Matsunami etc., Number (2000) 404:601-604; Li etc., Proc.Natl.Acad.ScLUSA (2002) 99:4962-4966; Montmayeur etc., NatureNeuroscience (2001) 4 (S): 492-498; United States Patent (USP) 6,462,148; PCT publication WO02/06254, WO00/63166art, WO02/064631 and WO03/001876; And U.S. Patent Publication No. US 2003/0232407 A1).
Yet T2R family has the family that surpasses 25 kinds of genes, and this family participates in the perception to bitter taste, and T1R family only comprises three member: T1R1, T1R2 and T1R3 (referring to Li etc., Proc.NatlAcad.ScL USA (2002) 99:4962-4966).Recently in WO 02/064631 and/or WO03/001876, disclose some T1R member when coexpression in suitable mammal cell line, can gather the functional taste acceptor of formation.Especially, have been found that T1R1 and the T1R3 coexpression in the suitable host cell can produce functional T1R1/T1R3 delicate flavour (" umami ") acceptor, this receptor stimulates the stimulation generation that comprises MSG to reply to delicate flavour.
Especially nearest, some publication is disclosed that and has been found that specific amide compound that this compounds can be used as the collaborative reinforcing agent of tasty agents and/or MSG " delicate flavour " very efficiently.
Yet, the application's applicant unexpectedly finds, similar to known multiple other artificial condiment, some new high efficiency compounds are compared the difference on can be flavoursome with MSG when concentration is higher, as can producing tempting secondary taste (mouth-watering side-tastes), long fragrance (flavor ＂ lingering "), or make tongue produce tingle or feeling of numbness sometimes.Although concerning some food formula, in fact need these secondary tastes (as spicy tartar sauce (hot and spicy sauce)), concerning other purposes, need to reduce or cover any secondary taste.If efficient umami compound is not disperseed in edible composition fully, then these secondary tastes just may become very obvious.And although the solubility of newfound high efficiency compound in water-based and polar organic media is very high, it is limited as the solubility in fat and the oil at hydrophobic/lipophilic substance, and hydrophobic/lipophilic substance is the natural constituents of many foods.Therefore, thereby effective prescription that will obtain new efficient umami compound is realized the optimal perceived of people to delicate flavour/delicate flavour, simultaneously secondary taste is minimized, this some the time be difficult.
Yet, when finding that it is safe new chemical entities (chemical entity) as new efficient umami compound (savory compound) time that the people is used, the original laboratory operation for preparing this compound at first may not be best mode for this compound of production commercial quantities.Also find the efficient tasty agents compound N-(2 of energy mass preparation in the prior art, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides and 2-H-benzo [3,4-d] 1, therefore the synthesis step of 3-dioxolanes-5-base-N-(propyl group butyl)-formamide has begun to develop method suitable, energy large-scale production above-claimed cpd.
For this reason, need to prepare delicate flavour adjusting prescription and/or delicate flavour and strengthen prescription, it can produce the delicate flavour of appreciable delicate flavour and/or enhancing MSG, avoids and/or overcome the problem of secondary taste and the existence of solubility aspect simultaneously, and such prescription can be used in the various uses.Composition that the present invention discloses and delicate flavour condiment concentrate composition and method can realize these beat all effects.
Summary of the invention
The invention discloses many-sided content, some aspect relates to the method for preparing edible composition, said composition contain have delicate flavour (" Umami ") the high efficiency compound or can be used as the high efficiency compound of sodium glutamate delicate flavour (" Umami flavor ") reinforcing agent; Some aspect relates to consumable products itself, and perhaps some aspect relates to improving one's methods of preparation or the described compound of purifying itself.
The content of above-mentioned discussion only is to the summary of some disclosure of the present invention, is not (also should not be construed) limitation of the present invention.
The specific embodiment
By with reference to following to each side of the present invention and the embodiment that comprised detailed description and with reference to chemical formula and form and in conjunction with before and can more easily understand the present invention to its description of carrying out afterwards.Before The compounds of this invention, composition and/or method are described and disclose, should be understood that, unless claims provide special explanation, otherwise the present invention is not limited to concrete food or food making method, concrete edible carrier or prescription, or be not limited to The compounds of this invention is mixed with the edible product of per os absorption or the ad hoc fashion of composition, because being perfectly clear, various equivalent modifications can adjust foregoing.It should be understood that equally the technology that the present invention uses only is used to describe particular rather than the present invention is limited.
Definition
" edible, biology can be used or pharmaceutically useful carrier or excipient " is solid or liquid medium and/or the composition that is used to prepare the required formulation of The compounds of this invention, described formulation makes The compounds of this invention take in dispersion/dilute form, thereby makes the biological effectiveness of The compounds of this invention reach maximum.Edible, biology can with or pharmaceutically useful carrier comprise many common food compositions, as neutral pH, the water of acid pH or alkaline pH, fruit juice or vegetable juice, vinegar, marinade (marinade), beer (beer), fruit wine (wine), natural water/fats emulsion such as milk or condensed milk, edible oil and shortening, aliphatic acid, the low-molecular weight oligo thing of propane diols, the glyceride of aliphatic acid and described hydrophobic substance dispersion liquid or the emulsion in water-bearing media, salt such as sodium chloride, flour, solvent such as ethanol, solid edible diluent such as vegetable powder or vegetables flour (vegetable powders or flours) or other liquid excipient; Disperse or suspension aids; Surfactant; Isotonic agent; Thickener or emulsifying agent, anticorrisive agent; Solid binder (solid binder); Lubricant etc.
" taste " of the present invention is meant the perception of study subject (subject) to taste and/or smell, comprises sweet, sour, salty, bitter, aquatic foods etc.Described study subject can be the human or animal.
" flavor enhancement " of the present invention is meant compound or its biologically acceptable salt that can induce taste or taste in the animal or human.
" taste conditioning agent " of the present invention is meant and can regulates (comprise and improve or strengthen) and the taste of inducing natural or synthetic flavor enhancement and/or compound or its biologically acceptable salt of smell in the animal or human.
" flavoring agent " of the present invention is meant and can strengthens or " raising " natural or the taste of synthetic flavor enhancement or compound or its biologically acceptable salt of smell.
" delicate flavour " of the present invention is meant the taste of that induced in the animal or human by MSG (sodium glutamate) usually, bright, tempting and delicious (" umami ").
" tasty agents " of the present invention or " umami compound " or " compound of activation umami receptor " are meant compound or its biologically acceptable salt that can produce appreciable delicate flavour in study subject, as, the MSG (sodium glutamate) that can activate external T1R1/T1R3 acceptor maybe can activate the compound of external T1R1/T1R3 acceptor.Described study subject is the human or animal.
" delicate flavour conditioning agent " of the present invention is meant compound or its biologically acceptable salt that can regulate (comprise and improve or strengthen) in the animal or human, induce and block the delicate flavour of natural or synthetic tasty agents such as sodium glutamate (MSG).
" flavour enhancer " of the present invention is meant and can strengthens in the animal or human, strengthen or compound or its biologically acceptable salt of the delicate flavour of " increase " natural or synthetic tasty agents such as sodium glutamate (MSG).
It is of the present invention that " compound of activation umami receptor " is meant the compound that can activate umami receptor (as the T1R1/T1R3 acceptor).
" regulating the compound of umami receptor " of the present invention is meant the compound that can regulate (activation, enhancing or blocking-up) umami receptor.
" strengthening the compound of umami receptor " of the present invention is meant and can strengthens or strengthen the compound natural or synthetic, that activate umami receptor such as the compound of sodium glutamate (MSG).
" amount of tasty agents " of the present invention is meant the compound of the delicate flavour that is enough to induce edible or pharmaceutically useful product or composition or the amount of its precursor.The very wide scope of the amount of tasty agents is about 0.001ppm to 100ppm, and narrow scope is that about 0.1ppm is to about 10ppm.Perhaps, the scope of the amount of tasty agents for about 0.01ppm to about 30ppm, about 0.05ppm about 15ppm, about 0.1ppm about 5ppm or about 0.1ppm about 3ppm extremely extremely extremely.
" delicate flavour regulated quantity " of the present invention is meant formula (I) compound of the delicate flavour that is enough to change (increase or reduce) edible or pharmaceutically acceptable product or composition or the amount of its precursor, and this change is enough to the perception by people's study subject institute.The very wide scope of delicate flavour regulated quantity is about 0.001ppm to 100ppm, and narrow scope is that about 0.1ppm is to about 10ppm.Perhaps, the scope of delicate flavour regulated quantity for about 0.01ppm to about 30ppm, about 0.05ppm is about 15ppm extremely, about 0.1ppm is about 5ppm or about 0.1ppm about 3ppm extremely extremely.
" delicate flavour enhancing amount " of the present invention is meant the compound amount that is enough to strengthen natural or synthetic flavor enhancement such as the taste of sodium glutamate (MSG) in edible or pharmaceutically acceptable product or composition.The very wide scope of delicate flavour enhancing amount is about 0.001ppm to 100ppm, or narrow scope is that about 0.1ppm is to about 10ppm.Perhaps, delicate flavour enhancing amount for about 0.01ppm to about 30ppm, about 0.05ppm is about 15ppm extremely, about 0.1ppm is about 5ppm or about 0.1ppm about 3ppm extremely extremely.
" umami receptor regulated quantity " of the present invention is meant the compound amount that is enough to regulate (activation, enhancing or blocking-up) umami receptor.The preferred range of umami receptor regulated quantity is 1pM to 100mM, more preferably is 1nM to 100 μ M, most preferably is 1nM to 30 μ M.The very wide scope of delicate flavour enhancing amount is about 0.001ppm to 100ppm, and narrow scope is that about 0.1ppm is to about 10ppm.Perhaps, delicate flavour strengthen weight range for about 0.01ppm to about 30ppm, about 0.05ppm is about 15ppm extremely, about 0.1ppm is about 5ppm or about 0.1ppm about 3ppm extremely extremely.
" the T1R1/T1R3 acceptor is regulated or volume of activation " is meant the compound amount that is enough to regulate or activate the T1R1/T1R3 acceptor.This tittle is preferably identical with the umami receptor regulated quantity.
" umami receptor " is the taste acceptor that regulated by umami compound.Preferably, umami receptor is a g protein coupled receptor, and more preferably, described umami receptor is the T1R1/T1R3 acceptor.
The compound that the present invention discloses can be regulated umami receptor, and is preferably the activator of T1R1/T1R3 acceptor.The activator of this receptor has the effect that the cascade of activation G protein signal is amplified.Under a lot of situations, described compound can produce appreciable delicate flavour to this activator effect of described acceptor equally in flavor tests.Therefore, wish that these compounds of the present invention can be used as the substitute of MSG, described compound is used in the food can not produce tolerance to some people.
In addition, this activator effect also can produce collaborative umami effects, and described collaborative umami effects produces when The compounds of this invention is united use with another kind of tasty agents such as MSG.Usually nucleotides IMP or GMP are added among the MSG strengthening the delicate flavour of MSG, thereby compare the amount that is reduced to the MSG that reaches identical umami effects and use relatively with independent use MSG.Therefore, The compounds of this invention need be united with another kind of tasty agents such as MSG and be added in edible composition or the prescription, this has advantageously eliminated and to have added expensive nucleotides such as IMP necessity as flavoring agent, simultaneously, compare with independent use umami compound or MSG, thisly unite use and can reduce or eliminate to reaching umami compound that identical umami effects uses such as the amount of MSG.
" synergy " is meant with the taste effect of each independent compound or the summation of seasoning effect and compares, and umami compound is united the umami effects of using the enhancing that brings.Using delicate flavour to strengthen under the situation of compound, synergy to the MSG effect can obtain proof by following data, and wherein: the EC50 ratio (as giving a definition) of formula (I) compound is 2.0 or higher, or is preferably 5.0 or higher, or 10.0 or higher, or 15.0 or higher.
Term " homogenizing " is meant any method (as reduce size and/or make the size homogeneous) that changes particle or droplet size under pressure, shearing and/or stress condition in fluid.Term " homogenizing " is intended to comprise multiple different homogenization process, and that these methods adopt is ultrasonic, pressure and/or mechanical force make the fluid homogenizing.The example of described homogenizing technology includes but not limited to two stage homogenisation (two-stage homogenization), high pressure homogenizing (high-pressure homogenization) (being also referred to as micronizing), super-pressure homogenizing (very highpressure homogenization) (VPH), rotor-stator homogenizing (rotator-statorhomogenization), blade homogenizing (blade homogenization), high-shear mixer (high shearmixers), ultrasonic (sonication), high shear impeller (high shear impeller), grinding (milling) etc.
When The compounds of this invention comprised one or more chiral centre, the spatial chemistry of described chiral centre can be R or S configuration independently, or the mixture of these two kinds of configurations.Described chiral centre is called after R or S or R, S or d, D, 1, L or d, 1, D, L further.Correspondingly, if there is the optical activity form in amide compound of the present invention, then these compounds can be in fact exist with the racemic mixture form of enantiomter, or exist with form purifying with that separate substantially separately with two kinds of isomers, or exist with the enantiomeric mixture form, wherein the relative scale of enantiomer is an arbitrary value in this mixture.
" hydrocarbon residue (hydrocarbon residue) " that the present invention uses is meant the chemical secondary group in the bigger compound, and the secondary group of described chemistry only has carbon atom and hydrogen atom.Described hydrocarbon residue can be aliphatic or aromatic, straight chain, ring-type, side chain, saturated or undersaturated.Yet, for described hydrocarbon residue, however name, it can or replace its carbon atom or hydrogen atom on its carbon atom or hydrogen atom and contain or be substituted with hetero atom such as O, S or N, or halogen (fluorine, chlorine, bromine and iodine), or contain heteroatomic substituting group (OH, NH
2, NO
2, SO
3H etc.).Therefore, when pointing out specially to contain these hetero atoms, or during with its called after " replacement ", described hydrocarbon residue also can contain carbonyl, amino, hydroxyl etc., or contains the hetero atom that is inserted in the hydrocarbon residue " skeleton ".
" the inorganic residue " that the present invention uses is meant and do not contain carbon but contain the residue that at least some hetero atoms comprise O, N, S, one or more halogen or alkali metal or alkaline-earth metal ions.Such example includes but not limited to H, Na
+, Ca
++And K
+, halogen, hydroxyl, NO
2Or NH
2
Term " alkyl ", " thiazolinyl " and " alkynyl " that the present invention uses comprise straight chain unit price substituting group and side chain unit price substituting group and ring-type unit price substituting group, and these substituting groups are respectively saturated and undersaturated (have at least one pair keys or have at least one triple bond).
＂ alkyl ＂ is meant alkyl, this alkyl can conceptive from alkane by from the structure of hydrocarbon compound, removing dehydrogenation and replacing described hydrogen atom to obtain with another atom or substituting group with straight or branched carbochain.In certain embodiments of the invention, described alkyl is ＂ C
1-C
6Alkyl ＂ is as methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, tertiary pentyl, hexyl etc.In certain embodiments of the invention, " C
1-C
4Alkyl " (or be referred to as " low alkyl group ") be methyl, ethyl, propyl group, isobutyl group, sec-butyl, the tert-butyl group and isopropyl.Some preferred alkyl of the present invention have 3 or more a plurality of carbon atom, preferably have 3-16 carbon atom, a 4-14 carbon atom or 6-12 carbon atom.
Preferred thiazolinyl is ＂ C
2-C
7Thiazolinyl ＂ such as vinyl, pi-allyl, 2-cyclobutenyl, 3-cyclobutenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl and straight chain diene and triolefin and alkadiene and triolefin.
Preferred alkynyl is ＂ C
2-C
7Alkynyl ＂ such as acetenyl, propinyl, 2-butynyl, valerylene base, 3-pentynyl, 2-hexin base, 3-hexin base, 4-hexin base, 2-heptyne base, 3-heptyne base, 4-heptyne base, 5-heptyne base and straight chain diine and three alkynes and alkadiyne and three alkynes.
Hydrocarbon residue can be chosen wantonly and be substituted.Two described optional substituting groups on the adjacent position can form aromatic series or non-aromatic, the saturated or undersaturated ring that is substituted that condense, optional together, and described ring is a 3-8 unit.Optional substituting group is generally hydrocarbon residue, and it can contain one or more hetero atoms or inorganic residue such as H, Na
+, Ca
++Or K
+
Term " alkyl of replacement "; " thiazolinyl of replacement "; " alkynyl of replacement " and " alkylidene of replacement " is meant alkyl; thiazolinyl; alkynyl and alkylidene (alkylene); described group is through one or more; preferably replace through one or two substituting group; described substituting group is preferably halogen; hydroxyl; the C1-C7 alkoxyl; alkoxyl-alkyl; oxo; the C3-C7 cycloalkyl; naphthyl; amino; (mono-substituted) amino; (dibasic) amino; guanidine radicals; heterocyclic radical; the heterocyclic radical that replaces; imidazole radicals; indyl; pyrrolidinyl; the C1-C7 acyl group; the C1-C7 acyloxy; nitro; carboxyl; carbamoyl; formamide; N-(C1-C6 alkyl) formamide; N, N-two (C1-C6 alkyl) formamide; cyano group; methyl sulphonyl amino; sulfydryl; C1-C4 alkylthio group or C1-C4 alkyl sulphonyl.The alkyl that replaces can replace one or many through identical or different substituting group, the preferred replacement once or twice.In many embodiments of the present invention, preferred substituted comprises hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.Contain in above-mentioned listed substituent a plurality of embodiments of the present invention, more preferred substituents comprises hydroxyl, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, methoxyl group and ethyoxyl.
The example of the above-mentioned alkyl that is substituted comprises 2-oxo-third-1-base; 3-oxo-Ding-1-base; cyano methyl; the nitro methyl; chloromethyl; methylol; the tetrahydropyran oxygen ylmethyl; trityl oxygen ylmethyl; the propionyloxy methyl; amino methyl; the carboxyl methyl; acrylic oxygen base carbonyl methyl; acrylic oxygen base carbonylamino methyl; methoxy; ethoxyl methyl; the tert-butoxy methyl; acetoxy-methyl; chloromethyl; trifluoromethyl; 6-hydroxyl hexyl; 2,4-dichloro (normal-butyl); the 2-aminopropyl; the 1-chloroethyl; the 2-chloroethyl; the 1-bromoethyl; the 2-chloroethyl; the 1-fluoro ethyl; the 2-fluoro ethyl; 1-iodine ethyl; 2-iodine ethyl; the 1-chloropropyl; the 2-chloropropyl; the 3-chloropropyl; the 1-bromopropyl; the 2-bromopropyl; the 3-bromopropyl; the 1-fluoropropyl; the 2-fluoropropyl; the 3-fluoropropyl; the 2-amino-ethyl; the 1-amino-ethyl; N-benzoyl-2-amino-ethyl; N-acetyl group-2-amino-ethyl; N-benzoyl-1-amino-ethyl; N-acetyl group-1-amino-ethyl etc.
The example of the above-mentioned thiazolinyl that is substituted comprises styryl, 3-chloro-propylene-1-base, 3-chloro-butene-1-Ji, 3-methoxyl group-propylene-2-base, 3-phenyl-butene-2-Ji, 1-cyano group-butylene-3-base etc.Geometric isomer is not crucial, and at the given thiazolinyl that is substituted, its all geometric isomers all can use.
The example of the above-mentioned alkynyl that is substituted comprises phenylacetylene-1-base, 1-phenyl 2-propine-1-base etc.
Term " oxo " is meant that a carbon atom with two other carbon atom bondings replaces through an oxygen atom, the two key bondings of this oxygen atom and a described carbon atom, thus form ketone group.
＂ alkoxyl ＂ is meant the OR group, and wherein R is the alkyl of alkyl or replacement." alkoxyl-alkyl " is meant the alkyl that contains alkoxyl.
Preferred alkoxyl is that " C1-C7 alkoxyl " is as methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, tert-butoxy etc.Term " alkoxyl that C1-C7 replaces " is meant that the moieties of alkoxyl can adopt the identical mode of alkyl that replaces with C1-C6 to be substituted.Similarly, term " C1-C7 phenyl alkoxyl " is meant " the C1-C7 alkoxyl " with the phenyl bonding.
" acyloxy " is meant the OR group, and wherein R is an acyl group.Preferred acyloxy is " a C1-C7 acyloxy " as formyloxy, acetoxyl group, propionyloxy, butyryl acyloxy, new pentane acyloxy, penta acyloxy, hexylyloxy, heptan acyloxy etc.
" acyl group " that the present invention uses contained the definition of alkyl, thiazolinyl, alkynyl and relevant hydridization form, and described group combines with other residue by carbonyl.Preferred acyl group is ＂ C1-C7 acyl group ＂ such as formoxyl, acetyl group, propiono, bytyry, valeryl, valeryl, caproyl, heptanoyl group, benzoyl etc.Preferred acyl group is acetyl group and benzoyl.
Cycloalkyl residues is the alkyl in the molecule, and described molecule contains at least one ring, and this ring has the continuous carbon atom that forms ring of 3-8 name.The example of described cycloalkyl residues comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group and saturated bicyclic ring alkane or saturated thick and polycyclic naphthene hydrocarbon such as naphthalane base, norcamphane base etc.Preferred cycloalkyl comprises that " C3-C7 cycloalkyl " is as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl or suberyl.Similarly, term ＂ C5-C7 cycloalkyl ＂ comprises cyclopenta, cyclohexyl or suberyl.
" cycloalkyl of replacement " is meant that above-mentioned cycloalkyl is substituted, and preferably replaces through one or two following group: halogen; hydroxyl; the C1-C4 alkylthio group; C1-C4 alkyl sulfoxide base (alkylsulfoxide); the C1-C4 alkyl sulphonyl; the alkylthio group that C1-C4 replaces; the alkyl sulfoxide base that C1-C4 replaces; the alkyl sulphonyl that C1-C4 replaces; the C1-C6 alkyl; the C1-C7 alkoxyl; the alkyl that C1-C6 replaces; C1-C7 alkoxyl-alkyl; oxo; (the single replacement) amino; (two replace) amino; trifluoromethyl; carboxyl; phenyl; the phenyl that replaces; thiophenyl; the phenyl sulfoxide group; phenyl sulfonyl and amino.In a plurality of embodiments of the cycloalkyl that replaces, the cycloalkyl of described replacement has 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, fluorine, chlorine, NH2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
Term " cycloalkylidene (cycloalkylene) " is meant cycloalkyl as defined above, and wherein cycloalkyl forms key two positions, and two extra groups that separate are linked together.Similarly, term " cycloalkylidene of replacement " is meant cycloalkylidene, and wherein cycloalkyl forms key two positions, two extra groups that separate is linked together, but also further contain at least one extra substituting group.
Term " cycloalkenyl group " is preferably 1,2 or 3-cyclopentene basic ring, 1,2,3 or 4-cyclohexene basic ring or 1,2,3,4 or 5-heptene basic ring, and term " cycloalkenyl group of replacement " is meant that above-mentioned cyclenes basic ring is substituted base and replaces, and described substituting group is preferably C
1-C
6Alkyl, halogen, hydroxyl, C
1-C
7Phenyl, amino or the amino of alkoxyl, alkoxyl-alkyl, trifluoromethyl, carboxyl, alkoxy carbonyl, oxo, (the single replacement) amino, (two replace) amino, phenyl, replacement through protecting.
Term " heterocyclic radical " or " heterocycle " are meant the optional 3-8 unit ring that is substituted, and described ring has one or more carbon atoms that are connected in the ring, and has 1-5 hetero atom such as oxygen, sulphur and/or nitrogen that is embedded in the ring.These 3-8 unit rings can be saturated, undersaturated or fractional saturation, but are preferably saturated." the amino heterocycle that replaces " is meant that above-mentioned arbitrary heterocycle is through at least one amino replacement.Preferred heterocycle comprises furyl, thio-furan base, piperidyl, pyridine radicals, morpholinyl, aziridine base, piperidyl, piperazinyl, tetrahydrofuran base, pyrrole radicals and tetrahydro-thienyl.
Term " heterocyclic radical of replacement " or " heterocycle of replacement " are meant that above-mentioned heterocycle is through for example one or more; preferably replace through one or two substituting group; described substituting group is identical or different and be preferably halogen; hydroxyl; sulfydryl; alkylthio group; cyano group; nitro; the C1-C6 alkyl; the C1-C7 alkoxyl; the alkoxyl that C1-C7 replaces; alkoxyl-alkyl; the C1-C7 acyl group; the C1-C7 acyloxy; carboxyl; alkoxy carbonyl; carboxymethyl; methylol; alkoxyl-alkyl; amino; (the single replacement) amino; (two replace) amino; formamide; N-(C1-C6 alkyl) formamide; N; N-two (C1-C6 alkyl) formamide; trifluoromethyl; N-((C1-C6 alkyl) sulfonyl) amino; N-(phenyl sulfonyl) amino, or above-mentioned heterocycle replaces through fused rings such as benzo ring.In a plurality of embodiments of the heterocyclic radical that replaces, the heterocyclic radical of described replacement has 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
" aryl " is meant group, di-ring (linked bicyclic) aromatic group or the aromatic group of fused bicyclic of monocyclic aromatic, this group comprises at least one 6 yuan of aromatic series " benzene " ring, preferably contain 6-12 carbon atom on the ring, described group such as phenyl, xenyl or naphthyl, described group can randomly replace through various organic and/or inorganic substituting groups, and aryl that wherein is substituted and substituting group thereof contain the 6-18 name altogether, or preferred 6-16 carbon atom.The preferred optional substituting group comprises 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
Term " heteroaryl " is meant the heterocyclic aryl derivative, and this derivative preferably contains 5-unit or 6-unit, has 1-4 heteroatomic conjugated aromatic ring system, and described hetero atom such as oxygen, sulphur and/or nitrogen, these hetero atoms are embedded in the described unsaturated conjugated heterocycle.Heteroaryl comprises bicyclic heteroaryl, di-ring heteroaryl or fused bicyclic heteroaryl.The example of heteroaryl comprises pyridine radicals, pyrimidine radicals and pyrazinyl, pyridazinyl, pyrrole radicals, furyl, thio-furan Ji, oxazolyl, isoxazolyl, phthalimido, thiazolyl, quinolyl, isoquinolyl, indyl, direct and phenyl, pyridine radicals or pyrrole radicals ring key close furans or thio-furan, or similar unsaturated conjugated heteroaromatic rings.Any bicyclic heteroaryl ring system, di-ring heteroaryl ring system or fused bicyclic heteroaryl ring system with aromatic series characteristic all is included in this definition, and wherein said aromatic series characteristic is that the distribution in whole ring system defines according to electronics.Usually, described heteroaromatic ring system contains 3-12 ring carbon atom and 1-5 hetero atom, and described hetero atom is independently selected from oxygen, nitrogen and sulphur.
Term " heteroaryl of replacement " is meant above-mentioned heteroaryl warp as one or more; preferred one or two identical or different substituting group replaces; described substituting group is preferably halogen; hydroxyl; hydroxyl through protection; sulfydryl; alkylthio group; cyano group; nitro; the C1-C6 alkyl; the alkyl that C1-C7 replaces; the C1-C7 alkoxyl; the alkoxyl that C1-C7 replaces; alkoxyl-alkyl; the C1-C7 acyl group; the acyl group that C1-C7 replaces; the C1-C7 acyloxy; carboxyl; alkoxy carbonyl; carboxymethyl; methylol; amino; (the single replacement) amino; (two replace) amino; formamide; N-(C1-C6 alkyl) formamide; N, N-two (C1-C6 alkyl) formamide; trifluoromethyl; N-((C1-C6 alkyl) sulfonyl) amino or N-(phenyl sulfonyl) amino.In a plurality of embodiments of the heteroaryl that replaces, the heteroaryl of described replacement has 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
The example of term " aryl alkyl of replacement " comprises group such as 2-phenyl-1-chloroethyl, 2-(4-methoxyphenyl) ethyl, 4-(2, the 6-dihydroxy phenyl)-n-hexyl, 2-(5-cyano group-3-methoxyphenyl)-n-pentyl, 3-(2, the 6-3,5-dimethylphenyl) propyl group, 4-chloro-3-aminobenzyl, 6-(4-methoxyphenyl)-3-carboxyl-n-hexyl, 5-(4-aminomethyl phenyl)-3-(aminomethyl)-n-pentyl, 5-phenyl-3-oxo-positive penta-1-base etc.
Term ＂ aryl alkylene ＂ is meant the aryl alkyl of above-mentioned definition, and there is bonding in wherein said aryl alkyl on two positions, and two extra groups that separate are linked together.This definition comprise as shown in the formula group :-phenyl-alkyl-and-alkyl-phenyl-alkyl-.Substituting group on the phenyl ring can be 1,2,1,3 or 1,4 replacement.Term " aryl alkylene of replacement " further preferably replaces through following group for aryl alkylene as defined above: halogen; hydroxyl; hydroxyl through protection; the C1-C4 alkylthio group; C1-C4 alkyl sulfoxide base; the C1-C4 alkyl sulphonyl; the alkylthio group that C1-C4 replaces; the alkyl sulfoxide base that C1-C4 replaces; the alkyl sulphonyl that C1-C4 replaces; the C1-C6 alkyl; the C1-C7 alkoxyl; the alkyl that C1-C6 replaces; C1-C7 alkoxyl-alkyl; oxo; (the single replacement) amino; (two replace) amino; trifluoromethyl; carboxyl; alkoxy carbonyl; phenyl; the phenyl that replaces; thiophenyl; the phenyl sulfoxide group; phenyl sulfonyl; on amino or the phenyl ring or on the alkyl through the amino of protection.
Term " phenyl of replacement " is meant through one or more; the preferred phenyl that replaces through one or two substituting group; described substituting group is preferably from halogen; hydroxyl; hydroxyl through protection; sulfydryl; alkylthio group; cyano group; nitro; the C1-C6 alkyl; the alkyl that C1-C6 replaces; the C1-C7 alkoxyl; the alkoxyl that C1-C7 replaces; alkoxyl-alkyl; the C1-C7 acyl group; the acyl group that C1-C7 replaces; the C1-C7 acyloxy; carboxyl; alkoxy carbonyl; carboxymethyl; methylol; amino; (the single replacement) amino; (two replace) amino; formamide; N-(C1-C6 alkyl) formamide; N; N-two (C1-C6 alkyl) formamide; trifluoromethyl; N-((C1-C6 alkyl) sulfonyl) amino; N-(phenyl sulfonyl) amino or phenyl; wherein said phenyl for replace or for being unsubstituted, thereby can obtain for example biphenyl.In a plurality of embodiments of substituted-phenyl, the phenyl of replacement has 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
Term " halo " and " halogen " are meant fluorine, chlorine, bromine or iodine atom.Can have one or more identical or different halogens.Preferred halogen is chlorine and fluorine.Although of the present invention a plurality of have halogen atom as substituent compound very effective aspect relevant taste acceptor, such halogenated organic compounds tends to produce bad toxicity after in animal is taken in body.Therefore, in a plurality of embodiments of formula (I) compound, if halogen atom is listed in (comprising the fluorine or chlorine atom) candidate's substituting group atom, then substituent alternative preferred group does not comprise halogen group, fluorin radical or cl radical.
Term " (the single replacement) amino " is meant the amino that replaces through a substituting group, phenylalkyl and heterocyclic radical that alkynyl, C7-C12 phenylalkyl, the C7-C12 that thiazolinyl, C2-C7 alkynyl, the C2-C7 that acyl group, C2-C7 thiazolinyl, the C2-C7 that alkyl, C1-C7 acyl group, the C1-C7 that described substituting group preferably replaces from phenyl, C1-C6 alkyl, the C1-C6 of phenyl, replacement replaces replaces replaces replaces.Described (the single replacement) amino can further have amino-blocking group, and defined by term " through (the single replacement) of protection amino " this moment.
Term " (two replace) amino " is meant that amino preferably replaces through two substituting groups, and described substituting group is selected from the phenylalkyl that alkyl, C1-C7 acyl group, C2-C7 thiazolinyl, C2-C7 alkynyl, C7-C12 phenylalkyl and C7-C12 that phenyl, C1-C6 alkyl, the C1-C6 of phenyl, replacement replace replace.These two substituting groups can be identical or different.
Term " alkylidene of replacement " is meant alkyl, and wherein this alkyl connects together two independent extra groups, and has extra substituting group at two position bondings.The example of the alkylidene that replaces comprises aminomethylene, 1-(amino)-1,2-ethylidene, 2-(amino)-1,2-ethylidene, 1-(acetylamino)-1,2-ethylidene, 2-(acetylamino)-1,2-ethylidene, 2-hydroxyl-1,1-ethylidene and 1-(amino)-1,3-propylidene.
One or more compound of the present invention can exist with the form of salt.The salt that the nitrogen of those and carboxylate anion and amine forms contained in term " salt ", and comprise the salt that forms with following organic and inorganic anion and cation.And term salt comprises the salt that forms by the reaction of standard Acid-Base with basic group (as amino) and organic or inorganic acid.Described acid comprises hydrochloric acid, hydrofluoric acid, trifluoroacetic acid, sulfuric acid, phosphoric acid, acetate, butanedioic acid, citric acid, lactic acid, maleic acid, fumaric acid, palmitic acid, cholic acid, pamoic acid, glutinous acid, D-glutamic acid, D-camphoric acid, glue acid, phthalic acid, tartaric acid, laurate, stearic acid, salicylic acid, methanesulfonic acid, benzene sulfonic acid, sorbic acid, picric acid, benzoic acid, cinnamic acid etc.
Term " organic or inorganic cation " is meant the carboxylate anion's of carboxylate counter ion (counter-ion).Described counter ion is selected from alkali metal and alkaline-earth metal (as lithium, sodium, potassium, barium, aluminium and calcium); Ammonium and single, two and trialkylamine such as Trimethylamine, cyclo-hexylamine; And organic cation, as dibenzyl ammonium, hexadecyldimethyl benzyl ammonium, 2-hydroxyethyl ammonium, two (2-hydroxyethyl) ammonium, phenylethyl hexadecyldimethyl benzyl ammonium, dibenzyl ethylene ammonium etc.Referring to, for example, ＂ Pharmaceutical Salts, ＂ Berge waits the people, J.Pharm.ScL (1977) 66:1-19, this article is hereby incorporated by.Other cation that above-mentioned term is contained comprises protonated form and basic amino acid such as glycine, ornithine, histidine, phenylglycine, lysine and the arginic protonated form of procaine, quinine and N-methyl glucoside amine.And, be also included within the scope of this term by any zwitterionic form of carboxylic acid with the amino The compounds of this invention that forms.For example, when R2 or R3 warp (quaternary ammonium) methyl substituted, just there is cation at the carboxylate anion.Cation at the carboxylate anion is preferably sodium ion.
The compounds of this invention also can adopt solvate and hydrate forms.Therefore, these compounds may be with the water of for example hydration or portion, many parts or any part parent solution solvents molecule crystallization.The solvate of these compounds and hydrate are all in protection scope of the present invention.
Term " amino acid " comprises any D-form in any one or the naturally occurring amino acid in naturally occurring 20 seed amino acids.In addition, except that D-amino acid, term ＂ amino acid ＂ also comprises other alpha-non-natural amino acid, and these alpha-non-natural amino acids are equal to natural amino acid on function.Such alpha-non-natural amino acid comprise as, norleucine (" NIe "), norvaline (" Nva "), L-or D-naphthalanine, ornithine (" Orn "), other amino acid that homoarginine (homoArg) and peptide field are known, as at M.Bodanzsky, ＂ Principles of Peptide Synthesis, the ＂ front page and second revision, Springer-Verlag, New York, NY, 1984 and 1993 and Stewart and Young, ＂ Solid Phase Peptide Synthesis, ＂ second edition, Pierce Chemical Co., Rockford, IL, those amino acid that disclose in 1984, these documents are incorporated this paper into as a reference.Amino acid and amino acid analogue can commerce be buied (Sigma Chemical Co.; Advanced Chemtech) or utilize that methods known in the art are synthetic to be obtained.
" amino acid side chain " is meant above-mentioned amino acid whose any side chain.
" replacement " in this article refers to part such as the hydrocarbon that is substituted, as alkyl that is substituted or benzyl, and wherein at least one element or group such as hydrogen replace through another element or group, replace through halogen as hydrogen in the benzyl chloride base.
The residue of the chemical substance of using in specification of the present invention and claims is meant structure fragment or group, it is that described chemical substance produces in specific reaction scheme or the follow-up formation of chemical products, does not need to consider that whether this structure fragment or group are really from described chemical substance.Therefore, the glycol residue in the polyester is meant the one or more-OCH in the polyester
2CH
2The O-repetitive, and do not consider whether described ethylene glycol is used to prepare described polyester.Similarly, 2 in the compound, 4-thiazolidinedione residue are meant one or more 2 in the described compound, 4-thiazolidinedione structure, and whether do not consider this residue by making 2, the reaction of 4-thiazolidinedione obtains described compound and obtains.
The organic residue ＂ of term ＂ is meant the residue of carbon containing, promptly contains the residue of at least one carbon atom, and includes but not limited to carbon-containing group, residue or group as defined above.Organic residue can contain various hetero atoms maybe can be by hetero atom and another molecular linkage, and described hetero atom comprises oxygen, nitrogen, sulphur, phosphorus etc.The example of organic residue includes but not limited to alkyl or substituted alkyl, alkoxyl or substituted alkoxy, list or disubstituted amido, amide group etc.Organic residue preferably contains 1-18 name carbon atom, 1-15 carbon atom, 1-12 carbon atom, a 1-8 name carbon atom or 1-4 carbon atom.
The term " effective dose " that uses at The compounds of this invention is meant that the amount of described compound is enough to desirable function is expected adjusting, the activation of described function such as taste acceptor, or the amount of described compound is enough to cause the taste perception.As will be described below needed exact amount can change with the variation of study subject like that, and this depends on species, age, health, specific identity and the pharmaceutical formulation etc. of study subject.Therefore, can not provide definite " effective dose ".Yet suitable effective amount can be determined by normal experiment by those skilled in the art.
It should be noted,, then comprise the plural implication of this noun if the noun that occurs in specification of the present invention and claims does not clearly provide opposite definition.Therefore, if mention " aromatic compound ", it comprises the mixture of aromatic compound.
Usually, the scope that occurs among the present invention is expressed as from " pact " particular value and/or to " pact " another particular value.When scope was so represented, another embodiment comprised from a described particular value and/or to described another particular value.Similarly,, should be understood to occurrence and formed another embodiment when being expressed as approximation by " pact " when numerical value.Will be understood that also the end value of each scope has significance difference each other apart from (significant), and independently of one another.
" optional " or " randomly " is meant that situation or the condition described thereafter may maybe can not take place, and described description has comprised the situation that described situation or conditional situation or described situation or condition do not take place.For example, phrase " the optional low alkyl group that is substituted " is meant that described low alkyl group may maybe can not be substituted, and described description has comprised low alkyl group that is unsubstituted and the low alkyl group that is substituted.
The delicate flavour amide compound of preparing
The a plurality of efficient umami compound that is used to prepare edible composition of the present invention comprises " acid amides " compound, these compounds are disclosed among U.S. Patent Publication No. No.US 2005/0084506 A1 and U.S. Patent Publication No. No.US 2006/0045953 A1 recently, purpose for the present invention's disclosure, these two pieces of applications all are incorporated herein by reference at this, but main purpose is described " acid amides " compound because of them, this amide compound has extraordinary effect as umami compound, and these two pieces of applications disclose the synthetic method and the synthetic embodiment of described amide compound, but also disclose described amide compound as tasty agents or flavor enhancement in the data aspect the biological effectiveness.The many delicate flavour amide compounds that are used in edible composition of the present invention and the prescription are organic (carbon containing) compound, these compounds all have at least one " acid amides " group, and have following general formula, described compound is defined as the amide compound with formula as follows (I) hereinafter:
The amide compound of formula (I) do not comprise known in biosystem or food naturally occurring any amide compound such as peptide, protein, nucleic acid, glycopeptide or glycoprotein etc.The amide compound of formula of the present invention (I) is artificial preparation and artificial synthetic amide compound.
For the various embodiments of general formula (I) compound, R
1, R
2And R
3Group further definition in several ways independently, that for example describes in detail in U.S. Patent Publication No. No.US 2005/0084506 A1 and U.S. Patent Publication No. No.US 2006/0045953 A1 is such, these two pieces of patent applications are hereby incorporated by, because they disclose and the structure of amide compound of the present invention and biologically active and the synthetic content relevant with purification process thereof.Therefore need be pointed out that specially, any subclass (subgenuses) of formula (I) compound that discloses among U.S. Patent Publication No. No.US 2005/0084506 A1 and U.S. Patent Publication No. No.US 2006/0045953 A1 and/or concrete material (species) all can be used in the following composition of the present invention, scheme and/or the method, thereby obtain improved food of delicate flavour or sweet taste or medicine, or their precursors.
At the many aspects of general formula (I) compound, R
1Comprise and have at least 3 carbon atoms and optional 1-20,1-15,1-10,1-8,1-7,1-6 or 1-5 heteroatomic organic residue or based on the residue of hydrocarbon, described hetero atom is independently selected from oxygen, nitrogen, sulphur, halogen or phosphorus.
At the many aspects of general formula (I) compound, R
2And R
3One of optional be hydrogen, and R
2And R
3In one or two comprise having at least 3 carbon atoms and optional 1-10 heteroatomic organic residue or based on the residue of hydrocarbon, described hetero atom is independently selected from oxygen, nitrogen, sulphur, halogen or phosphorus.
Many aspects at general formula (I) compound, the molecular weight of general formula (I) compound is less than about 800g/mol, in other related embodiment, described molecular weight is less than or equal to about 700g/mol, 600g/mol, 500g/mol, 450g/mol, 400g/mol, 350g/mol or 300g/mol.Similarly, formula (I) compound can have preferred molecular weight ranges, according to appointment the about 500g/mol of 175-, the about 450g/mol of about 200-, the about 400g/mol of about 225-, the about 350g/mol of about 250-.
For example, in some aspects, R
1, R
2And R
3Can be independently selected from aryl alkenyl, heteroaryl thiazolinyl, aryl alkyl, heteroaryl alkyl, alkyl, alkoxyalkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl ,-R
4OH ,-R
4OR
5,-R
4CN ,-R
4CO
2H ,-R
4CO
2R
5,-R
4COR
5,-R
4SR
5With-R
4SO
2R
5And the optional derivative that is substituted of described group, this derivative comprises 1,2,3 or 4 carbonyl, amino, hydroxyl or halogen group, wherein R
4And R
5Be the C1-C6 hydrocarbon residue.
In other related embodiment of the amidated compound of formula (I), R
1, R
2And R
3Can be independently selected from aryl alkenyl, heteroaryl thiazolinyl, aryl alkyl, heteroaryl alkyl, alkyl, alkoxyl-alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl, and the optional derivative that is substituted of described group, this derivative comprises 1,2,3 or 4 carbonyl, amino, hydroxyl, chlorine or fluorin radical.In the two class embodiments of just having mentioned, a cover is interchangeable to be independently to be selected from following substituting group with the preferred optional substituting group: hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
At the many aspects of formula (I) compound, R
2And R
3One of be hydrogen, another is organic residue or group.For example, at the many aspects of formula (I) compound, R
2And R
3In at least one be side chain or the organic residue of ring-type, this residue has directly and the nitrogen-atoms of (a) acyl ammonia and (b) carbon atom of two extra carbon atom Direct Bonding on other organic residue, wherein said other organic residue is side chain or the organic residue of ring-type, it contains other hydrogen atom and reaches 10 other carbon atom and 0-5 optional hetero atom, and this hetero atom is independently selected from oxygen, nitrogen, sulphur, fluorine and chlorine.Such side chain R
2And R
3Group comprises the organic residue with following structural formula:
N wherein
aAnd n
bBe independently selected from 1,2 and 3, each R
2aOr R
2bReplace residue and be independently selected from hydrogen, halogen, hydroxyl, or randomly contain 0-5 heteroatomic carbon containing residue, described hetero atom is independently selected from oxygen, nitrogen, sulphur and halogen.In some such embodiments, R
2aOr R
2bBe independent substituent, but in other embodiments, R
2aOr R
2bOne or more formation circuluses that are bonded together in the group.
Aspect some of formula (I) compound, R
2And R
3At least one be branched alkyl with 5-12 carbon atom, perhaps, R
2And R
3At least one be cycloalkyl or the cycloalkenyl group that contains 5-12 ring carbon atom.At R
2And R
3These embodiments in, branched alkyl or cycloalkyl or cyclenes basic ring can be randomly replace through 1,2,3 or 4 substituting group, described substituting group is independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical; R
9And R
10Be independently selected from H, alkyl, cycloalkyl and thiazolinyl.In some related fields, can be selected from hydroxyl, fluorine, chlorine, NH at the substituting group of described compound
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
At the many aspects of formula (I) compound, R
2Or R
3At least one be C
3-C
10Or C
3-C
15Branched alkyl.Have been found that these branched alkyls are very effective R concerning the delicate flavour amide compound
2Group.In others, C
3-C
10Branched alkyl can randomly be independently selected from following substituting group through one or two and replace: hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
Aspect some of formula (I) compound, R
2Or R
3At least one be cycloalkyl, cycloalkenyl group or heterocyclic radical saturated, that have 3-10 ring carbon atom, described group randomly is independently selected from following substituting group through 1,2 or 3 and replaces: NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, C
1-C
4Alkyl, C
1-C
4Haloalkyl, C
1-C
4Alkoxyl, C
1-C
4Halogenated alkoxy, hydroxyl and halogen.In other embodiments, R
2Or R
3At least one be cyclopenta, cyclohexyl, suberyl, ring octyl group or piperidyl, described group randomly independently is selected from following substituting group through 1,2 or 3 and replaces: hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
In some aspects, R
2Or R
3At least one be cyclohexyl, it is randomly through 1,2 or 3 methyl substituted.These examples through methyl substituted cyclohexyl are following structural formula:
Aspect some of formula (1) compound, R
2Or R
3At least one be 1-(1,2,3,4) tetralyl or 2 with following structural formula, 3-dihydro-1H-indenyl:
Or
Wherein m is 0,1,2 or 3, each R
2 'Can merge with aromatic ring or non-aromatic ring key and be independently selected from hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.Should be understood that optics and/or diastereo-isomerism can occur on these substituent cyclohexyl or the cyclopenta, different optics and/or diastereoisomer have different at least in a way biologically actives usually.
Aromatic series or heteroaromatic compound
In the many aspects of the formula with umami receptor agonist activity (I) amide compound, the present invention relates to have subclass as shown in the formula the aromatic amides compound of (II):
Wherein A comprises 5 or 6 yuan of aryl or heteroaryl ring; M is 0,1,2,3 or 4; Each R
1 'Be independently selected from alkyl, alkoxyl, alkoxyl-alkyl, hydroxy alkyl, OH, CN, CO
2H, CO
2R
6, CHO, COR
6, SR
6, halogen, thiazolinyl, cycloalkyl, cycloalkenyl group, heterocyclic radical, aryl and heteroaryl; R
6Be C
1-C
6Alkyl, R
2Can be above-mentioned any embodiment, or similar with it scheme.
In many aspects, the A group of formula (II) contains aryl rings, and promptly it contains at least one hexa-atomic phenyl (benzene) ring.Described aryl comprises benzene and naphthalene nucleus at least, and it can not be substituted, but in a plurality of embodiments, it is through at least 1,2 or 3 R
1 'Substituting group replaces, this R
1 'Substituting group is independently selected from hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
In certain preferred aspects, R
1 'Substituent one or two is bonded together, and forms saturated alkylidene dioxygen basic ring on benzyl ring, as following preferred structure (IIa) with (IIb):
R wherein
1a, R
1a 'And R
1bBe hydrogen or low alkyl group independently, or selectively, R
1aAnd R
1bBe hydrogen or methyl independently, or selectively, R
1aAnd R
1bAll be hydrogen.
The A group be the other example of fused bicyclic heteroaryl by (formula IIe) shown in the following benzoazole compounds and (formula IIf):
R wherein
1aOr R
1bBe hydrogen or low alkyl group independently.
In a plurality of embodiments of the amide compound of formula (II), A is the bicyclic heteroaryl ring.The bicyclic heteroaryl that can be used as A group in the formula (II) is represented by following structure:
Wherein m is 0,1,2 or 3, each R
1 'Be independently selected from hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
In a plurality of embodiments of the various subclass compounds of above-mentioned formula (II), R
1Or R
2At least one can be C
3-C
15Branched alkyl; The carboxylic acid lower alkyl esters of the carboxylic acid of alpha-substituted or alpha-substituted; Optional 5 or 6 yuan of aryl that replace through 1,2,3 or 4 substituting group or heteroaryl ring, described substituting group is independently selected from hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy; Cyclohexyl, it is optional through 1,2 or 3 methyl substituted; Or have 1-(1,2,3, a 4) tetralyl or 2 of following structural formula, 3-dihydro-1H-indenyl:
Wherein m is 0,1,2 or 3, each R
2 'Can close with aromatic ring or non-aromatic ring key, and be independently selected from hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy; Identical with above-mentioned description at general formula (I) amide compound.
In the many aspects that the present invention discloses, amide compound or its one or more edible salts of dropping in the following aromatic amides compound subclass scope can be used for preparing edible concentrate and/or final edible composition.
Wherein
I) A is 5 or 6 yuan of aryl or heteroaryl ring,
Ii) m is 0,1,2,3 or 4,
Iii) each R
1 'Be independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
Iv) R
2Have 3-15 carbon atom, and be branched alkyl, cycloalkyl or heterocyclic radical, described group is optional to be replaced through 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group.
The aromatic series of above-mentioned formula (II) or the subclass of heteroaromatic amide compound comprise multiple extraordinary activator at T1R1/T1R3 delicate flavour (" umami ") taste acceptor, these activators can be with low-down amide compound substrate concentration (micro-molar concentration or lower) effectively in conjunction with described acceptor, and can induce the people to produce appreciable delicate flavour sensation, and/or can be used as the reinforcing agent of MSG delicate flavour.
Therefore, when contacting with a variety of food and/or edible composition or its precursor, the multiple aromatic series or the heteroaromatic amide compound of formula (II) can be used as tasty agents or flavour enhancer, and be described as other place of the present invention.
The oxamides compound
In another subclass of formula (I) amide compound, described amide compound is for having the oxamides compound as shown in the formula (V):
R wherein
10And R
30Be selected from independently of one another and can contain one or more heteroatomic hydrocarbon residues, or preferably, R
10And R
30Be independently selected from aryl alkyl, heteroaryl alkyl, heterocyclic radical-alkyl or its optional group that is substituted and
R
20And R
40Maybe can contain one or more heteroatomic hydrocarbon residues for H independently of one another; Preferably, R
20And R
40Be H or C
1-C
3Alkyl, or its optional group that is substituted.More preferably, R
20And R
40Be H.And, for R
10And R
30, 0,1,2,3 or 4 optional substituting group can be arranged, described substituting group is independently selected from hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
In the preferred embodiment of the oxamides compound of formula (V), R
10And R
30Be independently selected from hydrocarbon residue, this residue has at least 3 carbon atoms and 1-10 optional hetero atom, and this hetero atom is independently selected from oxygen, nitrogen, sulphur, halogen or phosphorus, wherein R
20And R
40Be independently selected from hydrogen and hydrocarbon residue, this residue has at least 3 carbon atoms and 1-10 optional hetero atom, and this hetero atom is independently selected from oxygen, nitrogen, sulphur and halogen.
In the preferred embodiment of the oxamides compound of formula (V), R
20And R
40Be hydrogen.In such embodiments, R
10And R
30Can be independently selected from the aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl and the heterocyclic radical-alkyl that contain 5-15 carbon atom, wherein each R
10And R
30Can choose wantonly and contain 1-4 substituting group, described substituting group is independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
In a plurality of embodiments of the oxamides compound of formula (V), described oxamides compound has as shown in the formula (Va):
Wherein A and B are independently for containing aryl, heteroaryl, cycloalkyl or the heterocyclic radical of 5-12 annular atoms; M and n are 0,1,2,3 or 4-8 independently; R
20And R
40Be hydrogen, R
50Be the alkyl residue of hydrogen or alkyl or replacement, the alkyl of described alkyl or replacement comprises 1-4 carbon atom; R
60Do not exist or for C
1-C
5Alkylidene or C
1-C
5The alkylidene that replaces; R
70And R
80Be independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical; R
9And R
10Be independently selected from H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl and C
1-C
6Thiazolinyl.
In the preferred embodiment of the oxamides compound of formula (Va), R
60For-CH
2CH
2-group, A and B are independently selected from phenyl, pyridine radicals, furyl, thio-furan base and pyrroles's basic ring, and R
70And R
80Be independently selected from hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
In some embodiments of the oxamides compound of formula (Va), A and B are phenyl, pyridine radicals, furyl, benzofuranyl, pyrrole radicals, benzothienyl, piperidyl, cyclopenta, cyclohexyl or suberyl ring independently; M and n are 0,1,2 or 3 independently; R
20And R
40Be hydrogen; R
50Be hydrogen or methyl; R
60Be C
1-C
5Alkylidene, or be preferably C
2Alkylidene; R
70And R
80Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
In a plurality of embodiments of the oxamides compound of formula (V), described oxamides compound has the structure of formula (Vb):
Wherein A is phenyl, pyridine radicals, furyl, pyrrole radicals, piperidyl, cyclopenta, cyclohexyl or suberyl ring; M and n are 0,1,2 or 3 independently; R
50Be hydrogen or methyl; P is 1 or 2; R
70And R
80Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy, or two R
70Form (methylenedioxy) basic ring (methylenedioxy ring) together.In a plurality of embodiments of the oxamides compound of formula (Vb), described pyridine radicals-R
80Group has following structure:
Or
In some preferred embodiment of the oxamides compound of formula (V), described oxamides compound has formula (Vc):
Ar wherein
1Aryl or heteroaryl ring for the replacement that contains 5-12 carbon atom; R
50Be hydrogen or methyl; N is 0,1,2 or 3; Each R
80Be independently selected from hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.In some embodiments of the oxamides compound of formula (Vc), Ar
1Be 2-, 3-or the mono-substituted phenyl of 4-, 2,4-, 2,3-, 2,5-, 2,6-, 3,5-or 3, phenyl, trisubstd phenyl that the dibasic phenyl of 6-, 3-alkyl-4-replace, wherein said substituting group is independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy, or two adjacent substituting groups form the (methylenedioxy) basic ring together on benzyl ring.In some embodiment of the oxamides compound of formula (Vc), Ar
1Be the heteroaryl of the replacement that contains 5-12 carbon atom, and wherein said substituting group is independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
In some preferred embodiment of the oxamides compound of formula (V), described oxamides compound has formula (Vd):
Wherein A is aryl or the heteroaryl ring that contains the replacement of 5-12 carbon atom; R
50Be hydrogen or methyl; N is 0,1,2 or 3; Each R
80Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.Preferably, A is phenyl, pyridine radicals, furyl, pyrrole radicals, piperidyl, cyclopenta, cyclohexyl or suberyl ring, and described group randomly is independently selected from following substituting group through 1,2 or 3 and replaces: hydrogen, hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
In some embodiment of the oxamides compound of formula (V), described oxamides compound has formula (Ve):
Wherein m and n are 0,1,2 or 3 independently; R
70And R
80Be independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical; R
9And R
10Be independently selected from H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl and C
1-C
6Thiazolinyl.In related fields, R
70And R
80Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
Preferably, the pyridine radicals-R of the oxamides compound of formula (Ve)
80Group has following structure:
Or
At last, in aspect relevant some of method of the following delicate flavour concentrate composition of preparation, the oxamides compound of another subclass comprises compound with following structure or its one or more edible salt, and the oxamides compound of wherein said another subclass comprises the multiple efficient activator of T1R1/T1R3 delicate flavour (" umami ") taste acceptor:
Wherein:
I) A and B are aryl, heteroaryl, cycloalkyl or the heterocyclic radical that contains 5-12 annular atoms independently,
Ii) m and n are 0,1,2,3 or 4-8 independently,
Iii) R
70And R
80Be independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical; R
9And R
10Be independently selected from H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl and C
1-C
6Thiazolinyl, or two R
70Form the (methylenedioxy) basic ring together;
As passing through accompanying embodiment as can be seen, above-mentioned oxamides compound is extraordinary T1R1/T1R3 delicate flavour (" umami ") taste receptor stimulating agent, its can micro-molar concentration or lower concentration play a role, and can make the people produce appreciable delicate flavour sense, and/or can be used as the reinforcing agent of MSG delicate flavour.Therefore, when contacting with a variety of food and/or edible composition or their precursor, described oxamides compound can be used as tasty agents or flavour enhancer, as describing below.
Eat or medicinal compound
The multiple amide compound of formula (I) or its various subclass of enumerating comprise acidity or basic group, can exist with the form of salt according to the acidity of the edible or Pharmaceutical composition of preparing or basic character (" pH ") these compounds or subclass like this, preferred edible salts (promptly, generally believe it is safe, or GRAS) or pharmaceutical salts (wherein majority is by U.S. food and Drug Administration (Federal Foodand Drug Administration) approval).
Formula (I) amide compound with acidic-group such as hydroxy-acid group can tend to (near neutral physiological pH) and exist in solution with the form of carboxylate anion, therefore in preferred embodiments, also have relevant edible and/or pharmaceutically acceptable cation, these cations are well known by persons skilled in the art.Described edible and/or pharmaceutically acceptable cation comprise alkali metal cation (lithium ion, sodium ion and potassium ion), alkaline earth metal cation (magnesium ion, calcium ion etc.) or ammonium radical ion (NH
4)
+Or the ammonium radical ion of organic replacement is as (R-NH
3)
+
Formula (I) amide compound with alkali subtituent (as amino or nitrogen heterocyclic ring group) can tend to (in approaching neutral physiological pH, or in the common acid pH of many foods) exist in solution with the form of cation ammonium, therefore also have relevant edible and/or medicinal anion in preferred embodiments, many such anion are well known by persons skilled in the art.Described edible and/or medicinal anion comprises multiple anion of carboxylic acid form (anion salt of acetate, citric acid radical, tartrate anion, aliphatic acid etc.), halogen ion (particularly fluorine ion or chlorion), nitrate anion, or the like.
The amide compound of formula (I) and various subclass thereof should be preferably edible, promptly are considered to be suitable for being used in be used in the Foods or drinks taking in, and also should are pharmaceutically useful.Assert certain condiment compound whether edible usual method be that expert group by U.S.'s spices and extract producer association (Flavorand Extract Manufacturers Association) tests and/or assesses this compound, if qualified then be declared as " generally recognized as safe (Generally Recognized AsSafe) " (" GRAS ").FEMA/GRAS evaluation scheme at the condiment compound is very complicated, yet be that the food production those skilled in the art are known, related content is delivered people such as Smith, exercise question is ＂ GRAS Flavoring Substances 21, ＂ Food Technology, 57 (5), the 46-59 page or leaf is described in the article in May, 2003, and the whole content of this article is incorporated herein by reference.
When utilizing the FEMA/GRAS scheme to assess, usually whether to experimental rat have any harmful toxic and side effect at a kind of new condiment compound if will test it, this moment is high 100 times with the maximum acceptable concentration of advise employing than this compound in food particular types, approved, or high 1000 times or even higher concentration conditions under give such rat, feeding at least 90 days with described compound feeding.For example, test at amide compound of the present invention relates to described amide compound and the mixing of rat food, and give experimental rat such as Crl:CD (SD) IGS BR rat with its feeding, feeding concentration is about 100 mg/kg body weight/day, feeding 90 days, put to death then and assess, thereby illustrate that described general formula (I) compound does not have toxic and side effect to rat by various medical science method of testings.
Four compounds (following further describe in embodiment 1,24,26 and 30) are successfully by the test of FEMA-GRAS scheme, and have been declared as " generally recognized as safe ".
The compounds of this invention as flavour enhancer
Aforesaid formula (I) amide compound and all cpds subclass thereof and particular compound can be used as the umami compound or the taste conditioning agent of edible or medicinal product.Content that discloses from the present invention and embodiment as can be seen, many formulas (I) compound is hT1R1/hT1R3 " delicate flavour " receptor stimulating agent at least when high relatively amide compound substrate concentration.Therefore, a plurality of formulas (I) amide compound can be used as tasty agents or flavour enhancer with relative high concentration at least.
Yet, preferably use the least possible described artificial flavors, thereby reduce cost.And, also wish to develop edible composition, if above-claimed cpd just may produce described secondary taste when using with unnecessary high concentration with any " secondary taste ".Therefore, need test formula (I) compound as the validity of taste receptor stimulating agent when the low concentration, thus in affirmation formula (I) amide compound preferably and the most effective amide compound.As disclosing among WO 03/001876 and the U.S. Patent Publication application number No.US 2003-0232407 A1 and as mentioned below, existence at present can be measured the laboratory method of compound at the agonist activity of hT1R1/hT1R3 " delicate flavour " acceptor.Described method of testing is measured " EC usually
50", the concentration of promptly described compound activating 50% associated receptor.
Preferably, as described formula (I) amide compound of delicate flavour conditioning agent EC at the hT1R1/hT1R3 acceptor
50For less than about 10 μ M.More preferably, described amide compound is at the EC of hT1R1/hT1R3 acceptor
50Less than about 5 μ M, 3 μ M, 2 μ M, 1 μ M or 0.5 μ M.
In some embodiments, the amide compound of formula (I) is the delicate flavour conditioning agent or is the reinforcing agent of sodium glutamate to the agonist activity of hT1R1/hT1R3 acceptor.Described below is so-called EC
50The assay method of ratio promptly, is dissolved in formula (I) compound in the water that contains MSG, measures the degree that described amide compound reduces the amount that will activate the needed MSG of 50% effective hT1R1/hT1R3 acceptor.Preferably, when being dissolved in the aqueous solution of the sodium glutamate that contains the 1 μ M that has an appointment, the amide compound of described formula (I) can make the observation EC of sodium glutamate to hT1R1/hT1R3 acceptor (being expressed in HEK293-G α 15 clones)
50Reduce at least 50%, promptly described amide compound has at least 2.0, preferred 3.0,5.0 or 7.0 EC
50Ratio.
Above-mentioned identification experiment is used to discern the most effective formula (I) amide compound with regard to the character of delicate flavour conditioning agent or reinforcing agent, think that the delicate flavour perception of the reality that such result of experiment and animal and human produce can be fine relevant, but finally this result of experiment need be confirmed by the test of people's taste, is this situation at the most effective formula (I) compound at least.By tasting the candidate compound in aqueous solution, it is compared with contrasting aqueous solution, perhaps contain the real food compositions of amide compound of the present invention by trial test, can well quantize and control above-mentioned people's taste test experiments.
Therefore, in order to identify effectively delicate flavour conditioning agent or tasty agents, the aqueous solution Ying Jing that contains the amide compound of delicate flavour regulated quantity has great majority at least 8 people's taste testers' the group and is judged as and has delicate flavour.
Correspondingly, in order to identify effectively flavour enhancer, compare with the contrast aqueous solution that contains the 12mM sodium glutamate, contain the aqueous solution of formula (I) amide compound of delicate flavour regulated quantity and the 12mM sodium glutamate great majority in should group and be judged as delicate flavour with enhancing through having at least 8 people's taste testers.Preferably, in order to differentiate effectively flavour enhancer, compare with the contrast aqueous solution of 100 μ M inosine monophosphates with containing the 12mM sodium glutamate, contain the aqueous solution of formula (I) amide compound of delicate flavour regulated quantity (preferred about 30,10,5 or 2ppm) and the 12mM sodium glutamate great majority in should group and be judged as delicate flavour with enhancing through having at least 8 people's taste testers.
And, as described below, the flavor tests people has tasted several above-mentioned acid amides and/or the oxamides compound that is formulated into the test in the edible prescription of model, and write down described edible composition pointedly and have delicate flavour and/or good to eat feature (this feature is that the food that contains MSG has) really through regulating, particularly all the more so when described acid amides and/or oxamides compound can be dispersed in the described edible composition well, the concentration that adopts is the about 3ppm of about 0.1-, or the about 2ppm of about 0.2-.Therefore, when correct preparation and when being applied in suitable food and the new beverage, the seasoning purposes of above-claimed cpd includes but not limited to:
I. at condiment concentrate composition such as base-material (base), former soup (stock), seasoning mixture (seasoning mixe), in dissolubility yeast extract (autolyzed yeast extract) and hydrolyzed vegetable protein, strengthen delicate flavour, meat flavour and/or saline taste perception;
Ii. strengthen and improve the perfume intensity of the integral body/grinding/oleoresin extract of flavoring ingredients such as various odoriferous herbs;
Iii. strengthen food acid such as acetic acid, citric acid, malic acid, tartaric acid, phosphoric acid flavour strength and
Iv. novel delicate flavour is main taste (novel savory dimensional flavor), and it can strengthen strong (kokumi) taste and other taste based on the condiment of protein hydrolysate.Kokami is used to describe strengthen delicate flavour and make the lasting Japanese of delicate flavour.
Yet, if described acid amides and/or oxamides compound are not well dispersed in the described composition, perhaps these compound concentrations are too high, and described delicate flavour can be than the taste " lastingly " of MSG, and can feel the somatosensory of secondary taste of metal-like and/or fiber crops thorn sample.This " secondary taste " can be covered sometimes, but make peace evenly in order to guarantee one of taste, need carefully described compound to be operated, prepared and is added in " convenience type (user-friendly) " taste concentrate composition of dilution, this is easy to realize that these contents are also in the scope that the present invention discloses for traditional edible composition.Described condiment concentrate composition (flavorant concentrate composition) can be liquid or solid, perhaps can be made up of hydrophilic or hydrophobic taste thinner composition.
Delicate flavour acid amides of the present invention and/or oxamides compound have at least to a certain degree water-soluble usually, thereby be applicable to final use, by described delicate flavour acid amides and/or oxamides compound are dissolved in the aqueous solution that just can form delicate flavour acid amides and/or oxamides compound and/or MSG, AYE or HVP or other required composition in the water.Yet, by in edible organic solvent, making the concentration of described compound in the delicate flavour concentrate composition higher with other components dissolved described delicate flavour acid amides and/or oxamides compound.Therefore, in some aspects, the present invention relates to prepare the method for liquid delicate flavour condiment concentrate composition, comprising:
A) mix following substances with any order, contain at least about following one or more amide compounds of 10ppm or the liquid delicate flavour condiment concentrate composition of its edible salts thereby form:
I) contain the liquid phase of one or more edible solvents, described solvent is selected from benzylalcohol, triethyl citrate, Ergol, glyceryl triacetate (triacetin), glycerine, propane diols or its methyl ether or ethylether or its acetate,
Ii) sodium glutamate or glutamic acid and
Iii) one or more have amide compound or its one or more edible salts of following structural formula:
Wherein
(1) A is 5 or 6 yuan of aryl or heteroaryl ring,
(2) m is 0,1,2,3 or 4,
(3) each R
1 'Be independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
(4) R
2Have 3-15 carbon atom, and be branched alkyl, cycloalkyl ring or heterocyclic radical, described group is optional to be replaced through 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group.
In related fields, the present invention relates to prepare the method for liquid delicate flavour concentrate composition, comprising:
A) mix following substances with any order, contain at least about following one or more oxamides compounds of 10ppm or the liquid delicate flavour concentrate composition of its edible salts thereby form:
I) contain the liquid phase of one or more edible solvents, described solvent is selected from benzylalcohol, triethyl citrate, Ergol, glyceryl triacetate, glycerine, propane diols or its methyl ether or ethylether or its acetate,
Ii) sodium glutamate or glutamic acid and one or more have oxamides compound or its one or more edible salts of following structural formula:
Wherein
(1) A and B are aryl, heteroaryl, cycloalkyl or the heterocyclic radical that contains 5-12 annular atoms independently,
(2) m and n are 0,1,2,3 or 4-8 independently,
(3) R
70And R
80Be independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical; R
9And R
10Be independently selected from H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl and C
1-C
6Thiazolinyl, or two R
70Form the (methylenedioxy) basic ring together.
In many aspects, described liquid delicate flavour concentrate composition can contain one or more acid amides or oxamides compound or its edible salts of higher concentration, described concentration is that about 10ppm is to about 10,000ppm, about 50ppm be to about 5,000ppm, or about 100ppm is to about 1000ppm, the molar ratio that the total mole number of sodium glutamate or glutamic acid obtains divided by the total mole number of one or more amide compounds for about 5:1 to about 1000:1, or about 10:1 about 500:1 extremely, or about 20:1 about 300:1 extremely.In many aspects, described liquid delicate flavour condiment concentrate composition further comprises water.
And, as mentioned above, unexpectedly find, in relating to the seasoning purposes of liquid and/or semi-solid edible composition, the existence of aforesaid delicate flavour acid amides and/or oxamides compound can significantly strengthen the perception of people to salt (sodium chloride), thereby the sodium amount in the edible composition prescription is reduced.And, the edible composition prescription that existing known sodium amount reduces is to replace sodium chloride with potassium chloride (KCl), if but the concentration of potassium chloride is very big, it can cause producing metalloid secondary taste, the applicant finds that unexpectedly described acid amides and/or oxamides compound can partially or even wholly be covered this metalloid secondary taste.Therefore, in some aspects, the present invention relates to reduce the method for the sodium content in delicate flavour soup (savory soup), meat soup (broth), clear soup (bullion), tartar sauce (sauce) or the thick gravy (gravy) that contains sodium chloride and sodium glutamate, this method is passed through:
A) prepare existing soup (soup), meat soup, clear soup, tartar sauce, thick gravy or their precursor again, thereby make it contain the amide compound with following structural formula or its one or more edible salts at least about 0.01ppm:
Wherein
I) A is 5 or 6 yuan of aryl or heteroaryl ring,
Ii) m is 0,1,2,3 or 4,
Iii) each R
1Be independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
Iv) R
2Have 3-15 carbon atom, and be branched alkyl, cycloalkyl ring or heterocyclic radical, described group randomly replaces through 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group,
B) compare with existing soup, meat soup, clear soup, tartar sauce or thick gravy, reduce the amount of one or more sodium salts in soup, meat soup, clear soup, tartar sauce or the thick gravy that is added to described preparation again.
In related fields, the present invention relates to reduce the method for the sodium content in delicate flavour soup, meat soup, clear soup, tartar sauce or the thick gravy that contains sodium chloride and sodium glutamate, this method be by:
I) prepare existing soup, meat soup, clear soup, tartar sauce, thick gravy or their precursor again, thereby make it contain one or more oxamides compounds with following structural formula or its one or more edible salts at least about 0.01ppm:
Wherein
(1) A and B are aryl, heteroaryl, cycloalkyl or the heterocyclic radical that contains 5-12 annular atoms independently,
(2) m and n are 0,1,2,3 or 4-8 independently,
(3) R
70And R
80Be independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical; R
9And R
10Be independently selected from H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl and C
1-C
6Thiazolinyl, or two R
70Form the (methylenedioxy) basic ring together;
B) compare with existing soup, meat soup, clear soup, tartar sauce or thick gravy, reduce the amount of one or more sodium salts in soup, meat soup, clear soup, tartar sauce or the thick gravy that is added to described preparation again.
In described compound method again, compare with existing soup, meat soup, clear soup, tartar sauce or thick gravy prescription, the sodium amount that is added in soup, meat soup, clear soup, tartar sauce or the thick gravy that contains described amide compound is reduced by at least about 10wt%, or randomly reduce 15,20,25,30,35,40,45 or 50wt%, kept the good taste that the people can perception simultaneously.Salt content in soup, meat soup, clear soup, tartar sauce or the thick gravy of described preparation again is that the majority in the group through having at least 8 people's taste testers is judged as and compares on taste as broad as long with existing soup, meat soup, clear soup, tartar sauce or thick gravy ideally.
Others of the present invention relate to the method for preparing solid taste concentrate composition, comprise
A) provide one or more amide compounds or its one or more edible salts with following structural formula:
Wherein
I) A is 5 or 6 yuan of aryl or heteroaryl ring,
Ii) m is 0,1,2,3 or 4,
Iii) each R
1Be independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
Iv) R
2Have 3-15 carbon atom, and be branched alkyl, cycloalkyl ring or heterocyclic radical, described group randomly replaces through 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
B) described one or more amide compounds or its edible salts are dissolved in one or more edible liquid form seasoning soln;
C) described seasoning soln is contacted the formation midbody composite with one or more edible solid carriers or its solution, dispersion liquid or emulsion; With
D) thus make liquid from described midbody composite, remove or make liquid scatter and disappear to form the solid seasoning concentrate composition.
The similar aspect of the present invention relates to the method for preparing the solid seasoning concentrate composition, comprising:
A) provide one or more oxamides compounds or its one or more edible salts with following structural formula:
Wherein
I) A and B are aryl, heteroaryl, cycloalkyl or the heterocyclic radical that contains 5-12 annular atoms independently,
Ii) m and n are 0,1,2,3 or 4-8 independently,
Iii) R
70And R
80Be independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical; R
9And R
10Be independently selected from H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl and C
1-C
6Thiazolinyl, or two R
70Form the (methylenedioxy) basic ring together;
B) one or more oxamides compounds or its edible salts are dissolved in one or more edible liquid form seasoning soln;
C) described seasoning soln is contacted the formation midbody composite with one or more edible solid carriers or its solution, dispersion liquid or emulsion; With
D) thus from described midbody composite, remove or make it scatter and disappear to form the solid seasoning concentrate composition liquid.
In the method, at first described acid amides with efficient seasoning effect or oxamides compound are dissolved in and form seasoning soln in one or more edible liquid and described compound is diluted, wherein described seasoning molecule is dispersed or dissolved to lower and concentration homogeneous.The edible liquid that can be used for dispersing or dissolving described compound includes but not limited to water, ethanol, propane diols, glycerine, glyceryl triacetate, edible fat or edible oil, edible glycerol three esters, benzylalcohol, triethyl citrate and Ergol.
Then described seasoning soln is contacted with one or more edible solid carriers or its solution, dispersion liquid or emulsion and form midbody composite, can randomly further process to guarantee that described umami compound is dispersed in the described midbody composite to this midbody composite.Suitable solid carrier comprises edible polysaccharide such as native starch or modified starch (modified starch), Vegetable powder (vegetableflour), maltodextrin (maltodextrin), A type gelatin, the Type B gelatin, Quadrafos (polyphosphate), alginates (alginate), shitosan, carrageenan, pectin (pectin), starch, Arabic gum, ALA (alpha-lactalbumin), beta lactoglobulin (beta-lactoglobumin), ovalbumin (ovalbumin), polysorbate (polysorbitol), cyclodextrin, cellulose, methylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, milk powder (powdered milk), lactoprotein (milk protein), lactalbumin (whey protein), soybean protein (soy protein), rape albumen (canola protein), albumin, the gelatin that Jewish canon be can't help (kosher gelatin), the gelatin that Jewish canon is forbidden (non-kosher gelatin), the gelatin (non-Halal gelatin) that gelatin that islamic canon be can't help (Halal gelatin) and islamic canon are forbidden.
The further processing method of described midbody composite comprises that simple mixed method or more complicated and effective method are as grinding or homogenizing.Any homogenizing technology known in the art or equipment all can use, and many suitable homogenizers can commerce be buied.Homogenizing can relate to uses ultrasonic, pressure and/or plant equipment so that the fluid homogenizing.For example, described homogenizing can be two steps or two stage homogenisation, high pressure homogenizing, super-pressure homogenizing, rotor-stator homogenizing, blade homogenizing etc.
In some aspects, homogenization step can be based on the homogenizing technology of pressure, and this technology is about 500 to about 12, and 000psi, about 1,000 is to about 9, and 000psi or about 3,000 carries out under the pressure of 000psi to about 6.In other embodiments, described homogenization step can about 500,1000,1500,2000,2500,3000,3500,4000,4500,5000,5500,6000,6500,7000,7500,8000,8500,9000,9500,10000,10500,11000,11500 or the pressure of 12000psi under carry out, if wherein suitable, any described value all can form the upper limit or lower limit end points.Homogenizing can be used to produce evenly and/or smaller particle size, and is little of micron order or littler.
Described midbody composite can be through further processing, as sterilizing under solution, emulsion or fluid discrete form or pasteurization (pasteurize) after homogenizing.Also can add other composition such as sodium glutamate, inosine monophosphate, guanosine monophosphate, from dissolubility yeast extract, hydrolyzed vegetable protein, spices, stabilizing agent, buffer, antioxidant and other food additives and flavor enhancement commonly used.
In the method for above-mentioned discussion, at described midbody composite through processing with after guaranteeing that described acid amides or oxamides compound evenly disperse, liquid is removed or makes it lost from described midbody composite, thereby form the solid seasoning concentrate composition, said composition will be used for the final edible composition of seasoning.Scattering and disappearing of described liquid can or be evaporated realization by heating, or makes liquid effectively remove (active removal) by known method such as spray-drying, thereby forms final solid seasoning concentrate composition.Yet, still can remain with some liquid (as a spot of water, fat or oil) when described solid seasoning concentrate composition is in " solid " form even it should be noted that.
In many aspects of the present invention, the amount of described one or more amide compounds in described solid seasoning concentrate composition is about 100 to about 100,000ppm or 200 to 50,000,500 to 30,000,700 to 20,000 or 1000 to about 10,000ppm.
Some concrete processing problems when attempting to prepare the lipophilicity condiment concentrate composition that contains edible fat or oil, have been run into, wherein said acid amides and/or the solubility of oxamides compound in fat or oil are limited, therefore may exist to be not easy the dispersed solids form.Thereby a way that addresses this problem is to grind the mixture of described fat or oil and described acid amides or oxamides compound particle or it is carried out homogenizing to form microparticle dispersion.Therefore, some aspect of the present invention relates to the method for preparing lipophilicity delicate flavour condiment concentrate composition, comprising:
A) thereby one or more edible fats or oil are contacted formation precursor condiment mixture with amide compound or its one or more edible salts that one or more have following structural formula:
Wherein
I) A is 5 or 6 yuan of aryl or heteroaryl ring,
Ii) m is 0,1,2,3 or 4,
Iii) each R
1Be independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
Iv) R
2Have 3-15 carbon atom, and be branched alkyl, cycloalkyl ring or heterocyclic radical, described group randomly replaces through 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
B) the described precursor condiment mixture of processing forms lipophilicity delicate flavour condiment concentrate composition, and the major part at least of wherein said one or more amide compounds or its edible salts is with existing with undissolved particulate form of disperseing.
In related fields, the present invention relates to prepare the method for lipophilicity delicate flavour condiment concentrate composition, comprising:
A) thereby one or more edible fats or oil are contacted formation precursor condiment mixture with oxamides compound or its one or more edible salts that one or more have following structural formula:
Wherein
I) A and B are aryl, heteroaryl, cycloalkyl or the heterocyclic radical that contains 5-12 annular atoms independently,
Ii) m and n are 0,1,2,3 or 4-8 independently,
Iii) R
70And R
80Be independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical; R
9And R
10Be independently selected from H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl and C
1-C
6Thiazolinyl, or two R
70Form together the (methylenedioxy) basic ring and
B) the described precursor condiment mixture of processing forms lipophilicity delicate flavour condiment concentrate composition, and the major part at least of wherein said one or more amide compounds or its edible salts is with existing with undissolved particulate form of disperseing.
In the method, described procedure of processing contains following mechanical step usually: the particle size of described acid amides or oxamides compound is reduced in the desirable particle size scope of the compound that is dispersed in oil or the fat.Be dispersed in that desirable particle size scope can change according to the difference of final use in oil or the fat, but in a lot of the application, desirable particulate should have the average grain diameter less than about 100,50,40,30,20,10,5,2 or 1 μ m.
The mixture of umami compound
Have been found that, various acid amides and oxamides compound for the present invention's disclosure, although they all have extraordinary effect usually separately as tasty agents the time, these compounds also have dissolubility, delicate flavour induced velocity and the lasting degree of delicate flavour, secondary taste etc. in various degree respectively.The applicant unexpectedly finds, when compositions formulated, the umami effects of acid amides of the present invention and/or oxamides compound or delicate flavour strengthen effect and can be improved by the mixture that adopts one or both or multiple compound of the present invention.
Therefore, in some embodiments, the present invention relates to edible composition, it comprises
A) one or more amide compounds delicate flavour regulated quantity, that have following structural formula or its one or more edible salts:
Wherein
I) A ' is 5 or 6 yuan of aryl or heteroaryl ring,
Ii) m is 0,1,2,3 or 4,
Iii) each R
1 'Be independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group, one or two R
1 'Substituting group be bonded together form saturated alkylidene dioxygen basic ring and
Iv) R
2Have 3-15 carbon atom, and be branched alkyl, cycloalkyl ring or heterocyclic radical, described group randomly replaces through 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
B) one or more oxamides compounds delicate flavour regulated quantity, that have following structural formula or its one or more edible salts:
Wherein for described one or more oxamides compounds
I) A and B are aryl, heteroaryl, cycloalkyl or the heterocyclic radical that contains 5-12 annular atoms independently,
Ii) m and n are 0,1,2,3 or 4-8 independently,
Iii) R
70And R
80Be independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical; R
9And R
10Be independently selected from H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl and C
1-C
6Thiazolinyl, or two R
70Form the (methylenedioxy) basic ring together.
Not only containing the amidated compound but also contain in the oxamides compound compositions, said composition further comprises sodium glutamate (MSG) in a plurality of embodiments.In such composition, described acid amides and oxamides combination of compounds can strengthen the delicate flavour of the MSG that wherein exists, thereby reduce the amount of the needed MSG of the required umami effects level of realization and/or the amount of its relevant sodium ion, obtain more healthy edible composition simultaneously.
Not only containing the amidated compound but also contain in the oxamides compound compositions, described composition can contain has an appointment 0.1 to about 3ppm, or one or more amidated compounds and about 0.1 of about 0.2 to about 1ppm are to about 3ppm, or one or more oxamides compounds of about 0.2 to about 1ppm.In some embodiments, the total amount of described amide compound and oxamides compound is about 0.2 to about 3ppm, or about 0.5 to about 1.0ppm.Described acid amides and oxamides compound can exist with any molar ratio or part by weight, but in a plurality of enforcement sides amine, oxamides is extremely about 1:6 of about 1:1 to the part by weight of acid amides, or about 1:2 is to about 1:4.
The edible composition that contains the mixture of one or more amide compounds and one or more oxamides compounds can be any one in numerous classes, subclass and the concrete form of following edible composition, but in some preferably enforcement cases, described edible composition is clear soup, thick gravy or soup (soup); Or tartar sauce (sauce) or flavouring (condiment); Or vegetable juice or tomato juice or salad dressing (salad dressing) or mayonnaise; Or the delicate flavour seasoning composition, or hang the fried food of sticking with paste.
The composition that contains the mixture of one or more amide compounds and one or more oxamides compounds also can be the condiment concentrate composition.These condiment concentrate compositions can contain or can not contain MSG, and can contain and have an appointment 10 to about 10, one or more acid amides of 000ppm or oxamides compound.This condiment concentrate composition can be fluid composition or solid composite.
In some embodiments, the described edible composition that contains the mixture of one or more amide compounds and one or more oxamides compounds contains the amidated compound with following structural formula:
With the oxamides compound with following structure:
Utilize formula (I) compound edible composition
Condiment of the present invention, condiment conditioning agent, flavor enhancement, seasoning reinforcing agent, delicate flavour (" umami ") agent and/or flavour enhancer can be used for will using usually in food, beverage and the pharmaceutical composition of umami compound.These compositions comprise human composition and composition for animal consumption.It comprises the food that agricultural animal (agricultural animal), pet and zoo animal are edible.
Preparation and sale edible composition are (promptly, edible Foods or drinks, or its precursor or taste instrumentality) the routine techniques personnel be well understood to very much numerous classes, subclass or the concrete form of described edible composition, and can use the known generally acknowledged term in this field to describe these edible compositions, make great efforts exploitation simultaneously and sell these compositions.These terms in this field are following listed, need be pointed out that specially, the delicate flavour that the various subclass of formula (I) compound and concrete form can be used for regulating or strengthening following edible composition, these compounds can play a role or adopt its any rational combining form or form of mixtures to play a role separately, and described edible composition comprises:
Bakery (bread), pasta pastries (pastries), cakes (cakes), packaging / industrialized snacks
(Packaged / industrial cakes), unpackaged / handmade dessert (unpackaged / artisanal
cakes), biscuits (cookies), chocolate coated cookies (chocolate coated biscuits), sandwich cookies
(Sandwich biscuits), biscuit (filled biscuits), appetizer biscuits (savoury biscuits) and a thin
Crackers (crackers), bread substitutes (bread substitutes), breakfast cereals (breakfast
cereals), cereal (RTE cereals), family breakfast cereals (family breakfast cereals),
Oatmeal (flakes), the uncooked grains, nuts, dried fruit and other breakfast foods made by mixing
(Muesli), other cereal, children's breakfast cereals (children's breakfast cereals), heat
Cereal (hot cereals), dairy products (dairy products), milk (milk), fresh / pasteurized
Milk (fresh / pasteurised milk), whole fresh / pasteurized milk (full fat fresh / pasteurised
milk), semi-skimmed fresh / pasteurized milk (semi skimmed fresh / pasteurised milk), storability
Deposit / UHT milk (long-life/uht milk), fat-resistant storage / UHT milk (full fat long
life / uht milk), semi-skimmed storable / UHT milk (semi skimmed long life / uht milk),
Skim storable / UHT milk (fat-free long life / uht milk), milk (goat milk), concentrated cattle
Milk / condensed milk (condensed / evaporated milk), plain condensed milk / condensed milk (plain
condensed / evaporated milk), flavored condensed milk, condensed milk, and other functional concentrated cattle
Milk (flavoured, functional and other condensed milk), flavored milk drinks (flavoured
milk drinks), flavored milk drinks only milk (dairy only flavoured milk drinks),
Water, fruit juice flavored milk drinks (flavoured milk drinks with fruit juice), soy (soy
milk), yogurt drinks (sour milk drinks), fermented dairy beverages (fermented dairy drinks),
Coffee Mate (coffee whiteners), milk (powder milk), flavored milk drinks (flavoured
powder milk drinks), butter (cream), cheese (cheese), refined cheese (processed cheese),
Dispersible refined cheese (spreadable processed cheese), can not be dispersed refined cheeses
(Unspreadable processed cheese), unprocessed cheese (unprocessed cheese), divided
Scattered unprocessed cheese (spreadable unprocessed cheese), hard cheese (hard cheese),
Packed hard cheeses (packaged hard cheese), unpackaged dry cheese (unpackaged hard
cheese), yogurt (yoghurt), plain / natural yoghurt (plain / natural yoghurt), flavored yogurt
(Flavoured yoghurt), fruit-flavored yogurt (fruited yoghurt), probiotic yogurt (probiotic
yoghurt), drinkable yogurt (drinking yoghurt), regular drinking yogurt (regular drinking
yoghurt), probiotic drinking yogurt (probiotic drinking yoghurt), frozen dessert (chilled
snacks), fresh immature cheese (fromage frais) and quark cheese (quark), flavor of fresh unripe
Cheese and quark cheese (plain fromage frais and quark), flavored with fresh unripened cheeses and boast
G cheese (flavoured fromage frais and quark), an appetizer of fresh unripened cheese and milk quark
Casein (savoury fromage frais and quark), sweet canapes (sweet and savoury
snacks), fruit snacks (fruit snacks), potato chips / fries (chips / crisps), extruded
Dim Sum (extruded snacks), tortilla / corn chips (tortilla / Corn chips), popcorn (popcorn),
Pretzels (pretzels), nuts (nuts), other sweet canapes (sweet and savoury
snacks), snack bar (snack bars), cake salad bar (granola bars), breakfast cake bar (breakfast
bars), energy bars (energy bars), fruit pieces (fruit bars), other snack bar (snack bars), meals
Food substitutes (meal replacement products), diet food (slimming products), rehabilitation drink
Material (convalescence drinks), instant food (ready meals), canned ready meals (canned ready
meals), frozen instant food (frozen ready meals), dried instant food (dried ready meals),
Chilled ready meals (chilled ready meals), package (dinner mixes), frozen pizza (frozen
pizza), frozen pizza (chilled pizza), soup (soup), canned soup (canned soup), soup
(Dehydrated soup), instant soup (instant soup), chilled soup (chilled soup), UHT
Soup (UHT soup), frozen soup (frozen soup), pasta (pasta), canned pasta products
(Canned pasta), dried pasta products (dried pasta), chilled / fresh pasta products (chilled / fresh
pasta), pasta (noodles), plain noodles (plain noodles), instant noodles (instant noodles), cup
Loading / bowl of instant noodles (cups / bowl instant noodles), bags of instant noodles (pouch instant
noodles), cold noodles (chilled noodles), flavor noodles (snack noodles), canned food
(Canned food), canned meat and meat products (canned meat and meat products), canned fish / sea
Fresh (canned fish / seafood), canned vegetables (canned vegetables), canned tomatoes (canned
tomatoes), canned beans (canned beans), canned fruit (canned fruit), canned ready meals
(Canned ready meals) / canned soup (canned soup), canned pasta products (canned pasta), its
It canned food (canned foods), frozen food (frozen food), frozen processed red meat (frozen
processed red meat), frozen processed poultry (frozen processed poultry), frozen processed
Fish / seafood (frozen processed fish / seafood), frozen processed vegetables (frozen processed
vegetables), frozen meat substitutes (frozen meat substitutes), frozen potatoes (frozen
potatoes), baked potato chips (oven baked potato chips), other baked potato system
Goods (oven baked potato products), non-baked frozen potato (non-oven frozen
potatoes), frozen bakery products (frozen bakery products), frozen desserts (frozen
desserts), frozen ready meals (frozen ready meals), frozen pizza (frozen pizza), cold
Cold soup (frozen soup), frozen noodle (frozen noodles), other frozen foods (frozen food),
Dry foods (dried food), dessert platter (dessert mixes), dried instant food (dried ready meals),
Soup (dehydrated soup), instant soup (instant soup), dry pasta products (dried pasta), flavor
Noodles (plain noodles), instant noodles (instant noodles), cup / bowl of instant noodles (cups / bowl
instant noodles), bags of instant noodles (pouch instant noodles), frozen food (chilled food),
Refined refrigerated meat (chilled processed meats), frozen fish / seafood (chilled fish / seafood
products), frozen refined fish (chilled processed fish), frozen Guahu fish (chilled coated
fish), cold-smoked fish (chilled smoked fish), frozen lunch menu (chilled lunch kit), chilled
RTE foods (chilled ready meals), frozen pizza (chilled pizza), chilled soup (chilled soup),
Chilled / fresh pasta products (chilled / fresh pasta), cold noodles (chilled noodles), oil
And fats (oils and fats), olive oil (olive oil), plant and seed oils (vegetable and seed
oil), cooking fats (cooking fats), butter (butter), margarine (margarine), dispersible
Oils and fats (spreadable oils and fats), functional oils and fats can be dispersed (functional
spreadable oils and fats), sauces (sauces), sauce (dressings) and spices, tomato paste
And tomato sauce (tomato paste and purees), broth / stock cubes (bouillon / stock cubes), broth
Block (stock cubes), marinated particles (gravy granules), liquid broth and fonds (liquid stocks and
fonds), aromatic herbs (herbs and spices), fermented seasoning sauce (fermented sauces), based sauce
Oil sauce (soy based sauces), sauces (pasta sauces), wet sauce (wet sauces), dry sauce /
Powder mix (dry sauces / powder mixes), ketchup (ketchup), mayonnaise
(Mayonnaise), regular mayonnaise (regular mayonnaise), mustard (mustard), salad dressings
(Salad dressings), regular salad dressings (regular salad dressings), low-fat salad dressings (low
fat salad dressings), Vinaigrette (vinaigrettes), dipping (dips), pickles (pickled
products), other sauces (sauces), sauce (dressings) and condiments (condiments), Baby
Food (baby food), formula milk (milk formula), the standard formula (standard milk
formula), the second phase of formula (follow-on milk formula), children's milk formula (toddler
milk formula), low sensitivity formula (hypoallergenic milk formula), convenient baby food
Commodities (prepared baby food), dried baby food (dried baby food), other infant food,
Spreads (spreads), jam (jams) and pickled products (preserves), honey (honey), chocolate spread
Substance (chocolate spreads), nut spreads (nut-based spreads) and yeast spreads
(Yeast-based spreads).
...
Preferably, described formula (I) compound can be used for regulating or strengthening the delicate flavour of one or more following subclass edible compositions: candy (confectioneries), bread product (bakery products), dairy produce (dairy products), sweet taste appetizing dessert (sweet and savory snacks), dessert bar (snack bars), dietary substitute (meal replacement products), ready-to-eat food (ready meals), soup (soups), wheaten food (pastas), noodles (noodles), canned food (canned foods), frozen food (frozenfoods), dry food (dried foods), chilled food (chilled foods), oil ﹠ fat (oils and fats), infant food (baby foods), tablespread (spreads) or their mixture.Preferred food composition subclass is an edible composition listed in the following table:
| Product purpose | Sense organ and taste characteristic |
| Clear soup, meat soup, soup instant noodles | Delicate flavour, MSG taste profile and to the enhancing of delicate flavour, broth-like flavor and meat flavour |
| Low sodium meat soup, soup | Delicate flavour, the enhancing of delicate flavour, broth-like flavor and meat flavour, the disappearance of the peculiar smell of KCl such as bitter taste and metallic taste |
| The delicate flavour tartar sauce is as tartar sauce, thick gravy, cheese, beans sauce, flavouring based on tomato | The delicate flavour that strengthens, fragrant pungent, cheese flavor, delicate flavour and MSG taste profile; Flavoursome mixing and enhancing |
| Vegetable juice and tomato juice | The enhancing of delicate flavour, savoriness taste, the alleviating of tart flavour |
| Low sodium vegetable juice and tomato juice | The enhancing of delicate flavour, savoriness taste, the alleviating of the peculiar smell of KCl such as bitter taste and metallic taste |
| Salad dressing and mayonnaise | For cheese, the disappearance of ranch type taste, tart flavour and the blend of delicate flavour, for mayonnaise and high acid type flavouring, tart flavour is enhanced with delicate flavour |
| Garnishes: hang the French fried food of sticking with paste, fried appetizer, rice and potato garnishes | Delicate flavour and good to eat taste.The enhancing of fragrant pungent and delicate flavour.The taste profile of strengthening.Perception to sodium or salt strengthens |
| The local delicate flavour flavouring that is used for snack and French fried food etc. | Delicate flavour and good to eat taste.The enhancing of fragrant pungent and delicate flavour.The taste profile of strengthening. |
| The meat of pig, ox, sheep etc., poultry meat, flavouring of seafood and marinade | Delicate flavour and good to eat taste.The enhancing of fragrant pungent and delicate flavour.The taste profile of strengthening. |
Usually, the edible composition of production contains at least a compound or its various subclass in formula (I) scope capacity, above-mentioned, and the composition that obtains like this has desirable taste or taste profile as having " delicate flavour " feature.
Usually, the present invention is disclosed, one or more formulas (I) compound or the delicate flavour condiment concentrate composition of delicate flavour regulated quantity or delicate flavour dosage are added in edible or the medicinal product at least, thereby the edible or medicinal product that delicate flavour is regulated is compared delicate flavour and/or the sweet taste with enhancing with the edible or medicinal product that does not contain described amide compound, this point is judged by the human or animal usually, or under the situation of prescription test, by the majority approval of the group with at least 8 flavor tests persons, this judges by other local step of describing of the present invention.
Be used to regulate or strengthen certain can the changing of concentration of the delicate flavour flavor enhancement or the sweet taste flavor enhancement of edible or medicinal product or composition taste with various variablees, described variable comprise edible composition particular type, use which type of umami compound and concentration thereof, and specific compound is to the influence of these umami compound.Such as noted, the important use of formula (I) compound is to be used for regulating (induce, strengthen or suppress) other delicate flavour or sweet taste or other taste characteristic natural or synthetic tasty agents.The range of concentrations of common needed formula (I) amide compound is very wide, but numerical value is very little, promptly about 0.001ppm to 100ppm, or narrower selectable scope is from about 0.1ppm to about 10ppm, about 0.01ppm is to about 30ppm, about 0.05ppm is to about 15ppm, and about 0.1ppm is to about 5ppm, or about 0.1ppm is to about 3ppm.
The example that can add the Food ﹠ Drink of The compounds of this invention is wet soup class (Wet SoupCategory), dehydration and cooking food class (Dehydrated and Culinary Food Category), beverage class (Beverage Category), frozen food class (Frozen Food Category), snack categories (SnackFood Category) and flavouring and flavouring blend.
" wet soup class " is meant wet/liquid soup, and do not consider the concentration and the content of soup to comprise freezing soup.For this definition, soup is meant by the food of poultry meat, poultry meat, the flesh of fish, vegetables, cereal, fruit and the preparation of other composition, cooks in liquid, and this liquid may contain macroscopic of some or all of compositions in these compositions.Described soup can be (chunky), instant, half that concentrate or concentrate of (as meat soup) or dense (as assorted soup (chowder)) clearly, (smooth), dense thick (pureed) or stiff that silk is sliding, and can heat edible or freezing edible, can be used as the starter of a meal or as entree, or as snacks (between meal snack) (drinking as beverage).Soup can be used as the composition of other food of preparation, and can be to tartar sauce (cream soup or cheese soup) from meat soup (potage (consomme)).
" dehydration and cooking food class " is meant: (i) the culinary art supplement as: powder, particle, paste, concentrated fluid product comprise concentrated clear soup, the clear soup sample product of the piece of clear soup and compacting, sheet or powder or particle form (as finished product separately sale or as the composition in the product), tartar sauce and ingredients mixture (recipe mixes) (not considering technology); (ii) the meals solution product as: dehydration comprise the dehydrated soup compound, the instant powder that dewaters, instant powder (dehydratedready-to-cook soups), dehydration or normality convenience food goods (dehydrated or ambientpreparations of ready-made dishes), dinner and the human staple food (meals and single serveentrees) of boiling of dehydration comprise wheaten food, potato and rice (rice dishes) with powder freeze-drying; (iii) the canteen flavoring products is as flavouring, marinade (marinades), salad dressing (salad dressings), mayonnaise (saladtoppings), dip in sauce (dips), wrap up in powder (breading), batter compound (batter mixes), long shelf-life smear sauce (shelf stable spreads), barbecue sauce (barbecue sauces), liquid dish ingredients mixture (liquid recipe mixes), concentrate (concentrates), tartar sauce or tartar sauce mixture (sauces orsauce mixes) comprise the salad ingredients mixture, no matter they are with dehydration, which kind of form in liquid or the frozen form exists, can sell as finished product, or sell as the composition in the product.
＂ beverage class ＂ is meant beverage, beverage mix and concentrate, includes but not limited to the instant beverage and the dry beverage powder of alcohol or non-pure character.
Other example that can add the Food ﹠ Drink of The compounds of this invention comprises as soda and noncarbonated beverage products, as fruit syrup or vegetable juice, alcoholic beverage and non-alcoholic beverage, confectionary product (confectionaryproducts), as salad dressing and other flavouring, cereal and other breakfast food, tinned fruit and jam etc.
In addition, compound of the present invention can be used in the flavouring that will be added in the Food ﹠ Drink.In the preferred case, described composition can contain another kind of condiment or taste conditioning agent such as tasty agents.
The amide compound of formula (I) and various subclass thereof can with consumable products or medicinal product or its combination of precursors use described consumable products or medicinal product or its precursor in, the mode of adding is countless and be that all over the world the cook or the producer of edible or medicinal product is known.For example, the amide compound of formula (I) can be dissolved in or be dispersed in multiple edible liquid, in edible solid or other edible carrier, neutral pH for example, the water of acid pH or alkaline pH, fruit juice or vegetable juice, vinegar, marinade, beer, fruit wine, natural water/fat emulsion such as milk or condensed milk, edible oil and shortening, aliphatic acid, some low-molecular-weight oligomer of propane diols, the glyceride of aliphatic acid and dispersion liquid or the emulsion of these hydrophobic substances in water-bearing media, salt such as sodium chloride, Vegetable powder, solvent such as ethanol, solid edible diluent such as Vegetable powder or flour or the like, then with the combination of precursors of edible or medicinal product, or directly use in edible or the medicinal product.
Other food preparation and/or condiment application technology can be used to prepare The compounds of this invention, thus the preparation edible composition.With regard to " dry blend " particle, only need simply the efficient umami compound of the present invention or its solid seasoning concentrate composition with solid form and other condiment composition and/or carrier or mixing diluents, thereby produce the condiment powder of homogeneous ideally.Described carrier or diluent are known in the art, as maltodextrin, modified food starch, various hydrocolloid (hydrocolloid gum) as gum arabic (gum acacia), Arabic gum etc., or salt or sugar, these materials can be used singly or in combination.Composition through the correct dry blend of preparing should not be the particle of separated position, stratification state or released state, can make taste inhomogeneous or inconsistent like this.
In another embodiment, the solid seasoning concentrate composition can pass through method for congregating (agglomeration) preparation, and this method also claims bed process.In the method, compound of the present invention or its concentrate composition are coated on the diluent or carrier core substance particle (as edible polysaccharide, starch etc.) by sprinkling with the form of solid particle, and this diluent or carrier core substance particle is suspended in the flowing gas post (column of moving air) with control temperature and humidity.The bottom of particulate from reservoir device upwards arrives the top of container by aerosol (aerosol), this moving is at random, thereby The compounds of this invention evenly is coated on the core substance.Described particles coalesce (coalesce) forms porous aggregates.Final products are taken out from container, before packing, will pass through final drying steps and cooling step usually.Final aggregation substance is a kind of matrix, and it contains porous body (pore), crystalline solid (crystallization), concrement (coagulation) and/or condensate (polymerization).The gained coarse particles can be induced and be produced the seasoning effect and discharge reducing any " delicate flavour delays " of The compounds of this invention as hiding flavor, change the time that taste discharges or postponing taste, and/or adjusts delicate flavour and discharge with time/intensity and delicate flavour release with MSG and be complementary.
The another kind of hot condiment perfusion of technology right and wrong and complexing (non-thermal flavor infusion and complexing) technology that changes The compounds of this invention delicate flavour release characteristics.In this technology, the processing The compounds of this invention makes it through modified food starch (typically being beta cyclodextrin) complexing.Umami compound of the present invention is through the circulus complexing of modified starch, and delicate flavour discharges or the speed and the degree of the release of specific taste thereby change.Can adopt the whole bag of tricks to make cyclodextrin and The compounds of this invention complexing.Typically, use high-shear mixer or jolt device to make the The compounds of this invention dissolving, described cyclodextrin is added in the aqueous solution (typically being 20-40% water), remove by filter gained precipitation and complexation thing then.But gained pastel former state is used, and maybe can be dried or the grind into powder form.Aqueous paste can be with traditional air oven, spray dryer, vacuum desiccator, freeze-dryer and/or settler (agglomerator) drying.The dry aggregation method of long employing is freeze drying or vacuum drying, carries out under the relatively low like this baking temperature of 140-185 ℉.A selectable method is with solid cyclodextrin and the mode blend that integrates of condiment molecule.This mode has formed solid water/condiment molecular water pastel.Can directly use this pastel, or its further drying and grinding is formed powder type.This technology can reduce or increase " delicate flavour holdup time " (according to hobby of consumer) and/or improve delicate flavour and discharges to discharge with the time/intensity of MSG and delicate flavour and be complementary, and perhaps controls in order to be implemented in the various food formulas delicate flavour discharged.
Described liquid flavouring concentrate composition of the present invention can utilize liquid flavouring (LiqidFlavor Compounding) technology of mixing to be prepared usually, this technology comprises with umami compound as much as possible makes condiment concentration " high as far as possible ", reduces the amount of water in the liquid flavouring concentrate composition simultaneously as far as possible.
The preparation of formula (I) amide compound
The preparation The compounds of this invention is the various structure subclass of formula (I) amide compound and the initiation material of concrete material and synthetic precursor thereof, and the method for preparing above-claimed cpd is disclosed among U.S. Patent Publication No. No.US 2005/0084506 A1 and U.S. Patent Publication No. US 2006/0045953 A1, these two pieces of patent applications are hereby incorporated by, or as described below.
Synthetic method
Following proposal and embodiment are used to guide the reader, have also represented the whole bag of tricks of preparation amide compound of the present invention simultaneously.Disclosed method only is used for for example rather than limits, and those skilled in the art are very clear, and other method (much being known) can be used for preparing the amide compound in the various embodiments of the present invention.These methods comprise the chemical method based on solid phase particularly, comprise combinational chemistry.
Prepare acid amides by carboxylic acid and/or their derivatives (as ester, carboxylic acid halides etc.) with primary amine or secondary amine condensation, this carries out in the presence of dehydrating agent, coupling agent and/or appropriate catalyst usually.A large amount of suitable initiation materials can synthesize at an easy rate by the known method that document discloses as primary amine and secondary amine and carboxylic acid and their derivative, or these initiation materials obtains at an easy rate by commercial sources.In some cases, the method for synthetic certain amines or carboxylic acid initiation material is as described below.
Scheme 1a
Shown in scheme 1a, amide derivatives (I) can prepare by acid derivative (II) and amine (III) coupling, and this for example carries out in the presence of coupling agent such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride and alkali.In method A, (PS) carbodiimide that adopts polymer to support.The carbodiimide that method B adopts non-polymer to support.
Scheme 1b: the alternative method of preparation acid amides
X=halogen root
Shown in scheme 1B, amide derivatives (I) selectively is prepared by carboxylic acid halides, ester or acid anhydrides (IV) and amine (III) coupling in the presence of alkali.
For example, embodiment 1 compound as follows can be prepared by the method shown in embodiment 1 and the 1-1, then purifying.
In related fields, the invention discloses the 2-H-benzo [3,4-d] 1 that preparation embodiment 1 compound promptly has following structural formula, the method for 3-dioxolanes-5-base-N-(propyl group butyl)-formamide:
This improved method is compared with initial laboratory method has improved place, several places, and it has utilized a plurality of beat all discoveries, and this point will be described in detail subsequently.
Described method comprises:
A) make piperonylic acid (piperonylic acid) with following structural formula and the reagent reacting that can form acyl chlorides with carboxylic acid reaction:
Thereby form piperonyl acyl chlorides (piperonoyl chloride) with following structural formula:
Described reagent includes but not limited to thionyl chloride, oxalyl chloride and phosphoryl chloride phosphorus oxychloride (phosphorusoxychloride);
B) make step (a) piperonyl acyl chlorides that forms and 4-heptyl amine reaction form 2-H-benzo [3,4-d] 1,3-dioxolanes-5-base-N-(propyl group butyl)-formamide with following structural formula:
Step (a)
Step (a) relates to by piperonylic acid and forms the piperonyl acyl chlorides.Described piperonylic acid initiation material can be buied from manufacturer at an easy rate, for example Alfa Aesar GmbH ﹠amp; Co.
Alfa Aesar AJohnson Matthey
With Alfa Aesar Johnson Matthey
Step (a) has been utilized the reagent that can form the activation carbonyl group of acyl chlorides form with carboxylic acid reaction.The non-limiting reagent that is suitable for this step comprises thionyl chloride, oxalyl chloride and phosphoryl chloride phosphorus oxychloride, or their mixture.
For the formation of catalysis acyl chlorides, the reagent that can use a small amount of or catalytic amount as dimethyl formamide with increase reaction speed and obtain as described in acyl chlorides.
This reaction also can be carried out in the presence of solvent, and the non-limiting example of described solvent comprises and is selected from following solvent: carrene, chloroform and oxolane.
In some embodiments, step (a) also comprises one or more other steps:
I) piperonylic acid, carrene and dimethyl formamide are mixed the formation liquid mixture;
Ii) cool off described mixture to about 0 ℃ of mixture that forms cooling;
Iii) at about 10 ℃ or be lower than in the mixture that under about 10 ℃ of temperature the described reagent that can form acyl chlorides is added to described cooling and form reactant mixture; Or
Iv) add and heat described reactant mixture to refluxing after described acyl chlorides forms reagent, form the piperonyloyl solutions of chlorine.
Step (a) (i) relates to the use carrene as solvent, and uses dimethyl formamide to form the piperonyl acyl chlorides as catalyst in addition.
Step (a) (ii) relates to following reactions steps, wherein will be precooled to about 0 ℃ at the mixture that step (a) (i) forms before adding acyl chlorides formation reagent.
Step (a) (iii) relates to repeating step (iteration), and it is thionyl chloride that wherein said acyl chlorides forms reagent, and at about 10 ℃ or be lower than about 10 ℃ and add described thionyl chlorides.
Step (a) (iv) relates to the operator and can be chosen in and add the reactant mixture that behind the thionyl chloride step (a) is (iii) formed and add hot reflux to guarantee to be completed into the piperonyl acyl chlorides.
Step (a) also can be carried out in the presence of the above-mentioned organic base of the present invention, and described alkali is as acid absorbent (acid sponge).Many tertiary amines all are suitable for, and wherein triethylamine can be easy to buy, and price is not high yet, and are the organic bases that can use safely, have found that this alkali is applicable to the inventive method.
Step (b)
Step (b) relates to final products 2-H-benzo [3,4-d] 1, the formation of 3-dioxolanes-5-base-N-(propyl group butyl)-formamide, and comprise piperonyl acyl chlorides and the reaction of 4-heptyl amine that makes in step (a) formation.The 4-heptyl amine can be easy to buy from commerce.
By in the case, step (b) comprising in some enforcement sides:
I) 4-heptyl amine, triethylamine, carrene and dimethyl formamide are mixed formation 4-heptyl amine solution;
Ii) described piperonyl acyl chlorides is added in the described 4-heptyl amine solution being lower than about 5 ℃, forms reactant mixture; With
Iii) add thermal reaction mixture to about 20 ℃-Yue 25 ℃, form and contain 2-H-benzo [3,4-d] 1, the crude product reaction solution of 3-dioxolanes-5-base-N-(propyl group butyl)-formamide.
Step (b) (i) relates to the use carrene as solvent, also uses dimethyl formamide to be used to form end product as catalyst.
Step (b) (ii) relates to the once repetition (iteration) of reactions steps, wherein the piperonyl acyl chlorides is added in the solution that step (b) (i) forms being lower than about 5 ℃.
Step (b) (iii) relates to repeating step, and wherein the operator can be heated to solution for example about 20 ℃-Yue 25 ℃ and reacts completely guaranteeing.
Yet operator selectable is selected at step (b) and is added other step more in addition, for example,
Iv) cool off the crude product reaction solution that (iii) obtains in step (b) to about 0 ℃-Yue 5 ℃, add entry and form two phase liquid;
V) described two phase liquid is handled by the following method: remove water, adopt following order to handle the gained organic facies with following solution then:
1. has about 0.1N to the centinormal 1 aqueous hydrochloric acid solution of about 2.0N;
2. saturated aqueous solution of sodium bicarbonate; With
3. saturated aqueous sodium chloride;
Thereby form 2-H-benzo [3,4-d] 1,3-dioxolanes-5-base-N-(propyl group butyl)-formamide solution;
Vi) remove organic facies, form crude product 2-H-benzo [3,4-d] 1,3-dioxolanes-5-base-N-(propyl group butyl)-formamide; With
Vii) form crude product 2-H-benzo [3,4-d] 1, the slurries of 3-dioxolanes-5-base-N-(propyl group butyl)-formamide, isolated by filtration obtains 2-H-benzo [3,4-d] 1,3-dioxolanes-5-base-N-(propyl group butyl)-formamide.
According to operator's needs, these post-processing steps provide the method for separating required product.
Scheme 1c: the preparation of oxamides
As universal method, a kind of amine was reacted 0.5-2 hour with ethyl oxalate acyl chlorides (ethyl oxalyl chloride) in organic solvent in the presence of tertiary amine at ambient temperature, and described organic solvent is as diox, acetonitrile, oxolane, oxinane and dimethyl formamide.Add second kind of amine then, utilize oil bath with suspension 80 ℃ of heated overnight, or in microwave reactor 160 ℃ the heating 5 minutes.The gained reactant mixture can be through preparation property HPLC preparation, perhaps handle through moisture post-processing operation (aqueouswork-up), described crude product can carry out purifying through recrystallization, flash column chromatography or other method well known by persons skilled in the art usually and obtain pure oxamides.
(it is the R of formula (I) acid amides to various carboxylic acid derivates
1The appropriate precursors of group) and the various subclass of formula (I) amide compound can change the method preparation that obtains by method well known in the prior art or to these methods are simple, maybe can buy by commercial sources.Especially, often can buy by commercial sources as the aryl that is substituted or the heteroaryl carboxylic acid compound of formula (II) compound precursor, or by using known synthetic method to learn.Similarly, many amines as formula (I) amide compound appropriate precursors can be easy to obtain by the commercial channel, or obtain by known synthetic method.Yet what disclose in described scheme and/or following embodiment is to be used for synthetic R
1, R
2And R
3The method of the specific initial structure module of group (building block) precursor.
In some respects, the present invention relates to improving one's methods of synthetic above-mentioned oxamides compound and synthetic precursor thereof.
In some embodiments, the present invention relates to be used to prepare the method for N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides with following structural formula:
N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides is the high strength umami compound that new FEMA-GRAS ratifies, and it can replace or obviously strengthen the delicate flavour of sodium glutamate (MSG).Several places that the present invention's method disclosed here relates to known laboratory method improve, and it utilizes many beat all discoveries, will go through it below.
In some embodiments, described improving one's methods comprises:
A) make 2,4-dimethoxybenzylamine or its salt and 2-chloro-2-oxo acetic acid esters condensation in the presence of tertiary amine base and solvent or solvent mixture or aromatic solvent with following structural formula, described aromatic solvent comprises toluene, ortho-xylene, meta-xylene, paraxylene or nitrobenzene:
Have 2-(2,4-dimethoxy-benzyl the amino)-2-oxo acetate solution of following structural formula thereby form:
Wherein R is C
1-C
4The straight or branched alkyl; With
B) make 2-(2,4-dimethoxy-benzyl amino)-2-oxo acetate solution that forms in step (a) and 2-(pyridine-2-yl) ethamine reaction with following structural formula:
Thereby form N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides.
Step (a)
Step (a) relates to the formation of 2-(2,4-dimethoxy-benzyl the amino)-2-oxo acetic acid esters with following structural formula:
Wherein R is C
1-C
4The straight or branched alkyl.The operator who handles large-scale operation can understand extensive synthetic certain branch period of the day from 11 p.m. to 1 a.m and also will consider many problems and multiple variable factor.An important factor is the acquisition of initiation material.Method utilization of the present invention has the 2-chloro-2-oxo acetic acid esters of following structural formula:
Wherein R is C
1-C
4The straight or branched alkyl.This material can adopt method known to those skilled in the art to be prepared, and is prepared from the initiation material of easy acquisition, particularly oxalyl chloride and corresponding alcohol (methyl alcohol, ethanol, the tert-butyl alcohol etc.).Other advantage that these reagent have is that they can be prepared as required or can store for future use.Following embodiment 1 has adopted 2-chloro-2-oxo ethyl acetate.
Can be easily with 2, the 4-dimethoxybenzylamine stores with the form of its salt, for example with the form of ammonium salt, particularly with the form of hydrochloride and hydrobromate, described salt (comparing with the unhindered amina form) is oxidation-stabilized crystalline solid, has long storage life (shelf life).In addition, 2,4-dimethoxybenzylamine hydrochloride can be easy to obtain as initiation material, for example from Fisher
(cat. no No.AC17651-0050) buys.
Yet in the present invention, choice of Solvent is very important.With regard to experience, common rule is 10 ℃ of the every risings of reaction temperature, and reaction speed is original twice just.Although multiple other factors may slow down the increase of reaction speed under the specific range of temperatures condition in the reality, under the identical situation of all factors, it is fast more that temperature factor increases, and chemical reaction is complete more, and productive rate is also high more simultaneously.The invention discloses following beat all discovery, promptly have high boiling point and can be used for providing higher reaction speed and productive rate, and product treatment subsequently is simple, can finish by extraction with the not miscible aromatic solvent mixture of water.When the first step of this reaction containing in the following solvent one or more solvent or solvent mixture in when carrying out, the production capacity of this reaction is improved, gained solution can be at an easy rate through downstream, described solvent is toluene, ortho-xylene, meta-xylene, paraxylene, nitrobenzene, particularly toluene.
If the operator select by extract separate and/or purifying at the product that step (a) forms, then select a kind of separation that also can promote organic aqeous phase in these solvents or the solvent mixture.Especially, toluene can obtain from a lot of sale persons there with high purity and cheap price, and can be used to azeotropic remove any water that may exist after any optionally drying step.
Although 2, the 4-dimethoxybenzylamine can be used as free alkali, in order to reach several purposes, particularly for 2, the 4-dimethoxybenzylamine discharges from its hydrochloride, or the absorbent of any acid that forms in the conduct reaction, and step (a) can be carried out in the presence of organic base.Any can all be acceptable with non-reacted uncle's organic base of the sour coordination that discharges.Trialkylamine, tri-alkoxy amine or heteroaromatic amine are specially suitable alkali.The non-limiting example of trialkylamine comprises triethylamine, diisopropylethylamine and methyl diisopropylamine.The non-limiting example of tri-alkoxy amine comprises triethanolamine.The non-limiting example of heteroaromatic amine comprises pyridine and lutidines.Other non-nucleophilic amine, particularly 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene also can be used in the method for the present invention.Triethylamine can be easy to buy, and price is not high, and the organic base of being used safely, has found that it is applicable in the method for the present invention.
In enforcement side's amine, the step (a) of preparation N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides comprises:
A) in the presence of triethylamine and toluene, make 2,4-dimethoxybenzylamine or its salt and 2-chloro-2-oxo acetic acid ethyl reaction, this step also comprises one or more following steps:
I) with 2,4-dimethoxybenzylamine or its ammonium salt mix the formation mixture with triethylamine and toluene:
Ii) described mixture is cooled to about 0 ℃ of mixture that forms cooling;
Be about 10 ℃ or be lower than and in the mixture of described cooling, add 2-chloro-2-oxo ethyl acetate under about 10 ℃ condition iii), form reaction solution in the temperature that keeps described mixture; With
Iv) described reaction solution is warming to about 20 ℃ to about 27 ℃, forms impure 2-(2,4-dimethoxy-benzyl amino)-2-oxo ethyl acetate.
Step (a) (i) relates to and uses toluene as solvent, and uses triethylamine as the material that removes the HCl that dereaction generates, and when ammonium salt during as initiation material, triethylamine also can be used to discharge and dissociates 2, the 4-dimethoxybenzylamine simultaneously.
Step (a) (ii) relates to the once repetition of reactions steps, wherein the described mixture that will form before adding 2-chloro-2-oxo ethyl acetate is cooled to about 0 ℃, as step (a) (iii) described in, in this repeating step, 2-chloro-2-oxo ethyl acetate is about 10 ℃ or be lower than under about 10 ℃ of conditions and add in temperature.
Step (a) (iv) relates to last step of this repeating step, wherein will contain described impure 2-(2,4-dimethoxy-benzyl amino)-and the reaction solution of 2-oxo ethyl acetate and any unreacted initiation material is warming to about 20 ℃ to about 27 ℃, reacts completely guaranteeing.
In the further repetitive operation of step (a), this step also can comprise one or more other steps:
V) in the solution of 2-(2,4-dimethoxy-benzyl amino)-2-oxo acetic acid esters, add aqueous hydrochloric acid solution, form water and the organic liquid phase that contains described 2-(2,4-dimethoxy-benzyl amino)-2-oxo acetic acid esters;
Vi) the drying described organic liquid that contains described 2-(2,4-dimethoxy-benzyl amino)-2-oxo acetic acid esters forms the anhydrous solution of 2-(2,4-dimethoxy-benzyl amino)-2-oxo acetic acid esters mutually.
Such extraction step can be used for removing any water-solubility impurity or removes the salt that forms in first reactions steps (a).
If desired or be necessary, described intermediate can be before reaction through purifying fully, the operator also can select to add following step at step (a):
Vii) from the anhydrous toluene solution of described 2-(2,4-dimethoxy-benzyl amino)-2-oxo ethyl acetate, remove toluene, form 2-(2,4-dimethoxy-benzyl amino)-2-oxo ethyl acetate solid; With
The viii) described 2-of purifying (2,4-dimethoxy-benzyl amino)-2-oxo ethyl acetate solid.
The operator can be appreciated that the step of these interpolations makes the user of the inventive method face all more options, and whether one of them select purify intermediates 2-(2,4-dimethoxy-benzyl amino)-2-oxo ethyl acetate exactly.This selects particular importance, because the end product of the inventive method is a tastant, it all is used in a plurality of application in the food of taking in for the people possibly.Therefore, described final step is necessary to carry out on the equipment different with the equipment that carries out step (a).Adopt purified intermediate can make the operator in another equipment or the reactor that separates, finish method of the present invention.
Step (b)
Step (b) relates to end product N-(2, the 4-dimethoxy-benzyl)-formation of N '-[2-(pyridine-2-yl) ethyl] oxamides, comprise and make 2-(2,4-dimethoxy-benzyl amino)-2-oxo acetic acid esters that forms in step (a) and 2-(pyridine-2-yl) ethamine reaction with following structural formula:
Equally, if the operator needs, this step can adopt for example toluene of aforementioned solvents.And, to the fact that the selection of the step that forms end product has utilized 2-(2-amino-ethyl) pyridine to buy easily, for example can be from ABCR GmbH ﹠amp; Co.KG, Chemos GmbH, Connect Marketing GmbH and Rich Fine Chemicals Co., Ltd buys.
Other embodiment of the method for preparation N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides relates to following step, and wherein step (b) comprises following one or more step:
I) 2-(2-amino-ethyl) pyridine is mixed in the solution of step (a), form reaction solution and
Ii) heat described reaction solution and form N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides.
The solution that step (b) (i) has utilized step (a) to obtain, described solution does not carry out any optional post-processing step.
Step (b) (ii) allows the operator that the temperature range of reacting is selected, and for example, the solution of the toluene solvant with higher is refluxed, and toluene is used as solvent in step (a), thereby increases reaction yield.
Therefore, in some embodiment of step (b), this step also can comprise the steps:
Iii) described reaction solution cooling is formed the cooling solution of N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides;
Iv) from described cooling solution, solidify described N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides by adding dialkyl ether; With
V) collect described N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides solid.
Yet, carrying out to selecting property of operator selectable this step, this just means that other step also can be used for separating end product.For example, other step that can be used for improving productive rate and/or purity comprises:
Vi) handle at step (b) (N-that vi) obtains (2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides solid, formation N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides slurries with hexane; With
Vii) from described slurries, collect described N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides, form pure N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides.
On the other hand, the present invention relates to prepare the method for N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides, comprising:
A) will have 2 of following structural formula, 4-dimethoxybenzylamine or its ammonium salt are dissolved in and form mixture in triethylamine and the toluene:
B) about 10 ℃ or be lower than about 10 ℃ in the described mixture that step (a) forms, adding 2-chloro-2-oxo ethyl acetate with following structural formula:
Formation has 2-(2,4-dimethoxy-benzyl the amino)-2-oxo ethyl acetate of following structural formula:
C) make 2-(2,4-dimethoxy-benzyl amino)-2-oxo ethyl acetate that forms in step (b) and 2-(pyridine-2-yl) ethamine reaction form reaction solution with following structural formula:
Then, heat described reaction solution and form N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides: and
D) randomly, the product of separating step (c) as follows:
I) described reflux solution is cooled to about 25 ℃ to about 35 ℃, forms N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides cooling solution;
Ii) from described cooling solution, be settled out described N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides by adding methyl tertiary butyl ether(MTBE); With
Iii) collect described N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides.
Other oxamides compound that the present invention discloses can adopt with the similar method of the method for above-mentioned disclosure and be prepared.
The present invention discloses, and synthetic other improve one's methods relates to improving one's methods of preparation initiation material.
For example, some aspect of the present invention relates to improving one's methods of preparation 2-methoxyl group-4-methyl-benzylamine or its salt, and it is undertaken by reaction sequence as described below:
A) with methylating reagent 2-hydroxy-4-methyl-benzamide is methylated, obtain 2-methoxyl group-4-methyl-benzamide; With
B) with hydride reduction reagent reductase 12-methoxyl group-4-methyl-benzamide, obtain 2-methoxyl group-4-methyl-benzylamine or its salt, shown in following scheme:
In the method for this production oxamides compound precursor, described methylating reagent can comprise all ingredients well known by persons skilled in the art, as methyl halide, dimethyl suflfate, toluenesulfonic acid methyl esters etc.Similarly, can be optionally be that the various hydride reducers of amine are (as lithium aluminium hydride reduction with the carbonyl reduction of acid amides, the diisobutylaluminium hydride lithium, lithium tri-t-butoxyaluminium hydride or hydrogenation two (2-methoxy ethoxy) aluminium sodium or similar boron hydride reagent) also be well known in the art.Referring to embodiment 30-1.
Similarly, the invention still further relates to the method for other precursor of preparation oxamides compound, as prepare shown in the method for 2-(5-picoline-2-yl) ethamine or its salt like that, it comprises
A) handle acetonitrile removing hydrogen ion wherein with highly basic,
B) make the acetonitrile condensation of 2-bromo-5-picoline and alkali treatment obtain 2-(5-picoline-2-yl) acetonitrile; With
C) cyano group of reductase 12-(5-picoline-2-yl) acetonitrile obtains 2-(5-picoline-2-yl) ethamine or its salt.This method is shown in following scheme:
In such method, a hydrogen atom of acetonitrile can be removed through very strong alkali (as the lithium salts of lithium alkylide or aryl lithium or dialkylamine), produce the high nucleophilicity organic metal salt of acetonitrile, it can be at an easy rate falls halogen from aryl halide such as the displacement of 2-bromo-5-picoline and obtains 2-(5-picoline-2-yl) acetonitrile, this compound can be through various known stoichiometric hydride reducers, or obtain corresponding 2-(5-picoline-2-yl) ethamine by the catalytic hydrogenation reduction.The catalyst that is used for above-mentioned catalytic hydrogenation is Raney Ni (Raney nickel).
At last, final oxamides compound can obtain by condensation oxamides precursor (as implied above) is synthetic successively.For example, adopt " one kettle way " preparation, as following describing in detail among the embodiment 30-1.
This preparation N
1-(2-methoxyl group-4-methyl-benzyl)-N
2-(2-(5-picoline-2-yl) ethyl) oxamides " one kettle way " comprising:
A) make the reaction of 2-methoxyl group-4-methylbenzylamine and 2-chloro-oxo acetic acid esters obtain N-(2-methoxyl group-4-methyl-benzyl)-oxalic acid acid amides ethyl ester (N-(2-methoxy-4-methyl-benzyl)-oxalamic acidethyl ester); With
B) make the reaction of N-(2-methoxyl group-4-methyl-benzyl)-oxalic acid acid amides ethyl ester and 2-(5-picoline-2-yl) ethamine obtain N
1-(2-methoxyl group-4-methyl-benzyl)-N
2-(2-(5-picoline-2-yl) ethyl) oxamides.
Two steps of " one kettle way " are carried out in single solvent such as acetonitrile and gentle organic or inorganic alkali such as triethylamine usually.Yet the applicant unexpectedly finds, can obviously improve yield sometimes by adopt separation and purification step between two steps, as described in embodiment 30-2.
At last, the applicant finds, many acid amides of the present invention and/or oxamides compound major part are insoluble at the height apolar medium in as hydrocarbon, fat or oil, but can and heat the heptane and the ethyl acetate mixture solution of described compound by dissolving usually, cool off this solution then and advantageously be recrystallized and obtain highly purified product.Especially, as embodiment 30-2 describes in detail, the present invention relates to N-(heptan-4-yl)-benzo [d] [1,3] dioxole-5-formamide is carried out the method for crystallization, comprising:
C) composition dissolves that will contain N-(heptan-4-yl)-benzo [d] [1,3] dioxole-5-formamide at high temperature forms solution in ethyl acetate and heptane: and
D) cooling gained solution, thus the solid that contains N-(heptan-4-yl)-benzo [d] [1,3] dioxole-5-formamide formed.
In a plurality of embodiments of described purification process, crystallization is carried out in dry nitrogen atmosphere, dissolving step is to carry out to about 60 ℃ temperature at about 40 ℃, then gained solution is cooled to about 0 ℃ to about 30 ℃, the solid crystal of resulting separation then, drying obtains desciccate, and it can be a purity greater than 99% N-(heptan-4-yl)-benzo [d] [1,3] dioxole-5-formamide.
Measure the biologically active of The compounds of this invention
Technology and analytical method based on cell, as disclosing in WO 02/064631 and WO 03/001876 and U.S. Patent Publication No. No.US 2003/0232407 A1 those just are used for coming elementary screening classes of compounds to T1R1/T1R3 " delicate flavour " taste acceptor or to the agonist activity or the antagonist activities of T1R2/T1R3 " sweet taste " the taste acceptor of expressing in suitable clone.In case amide compound obtains initial ＂ and hits (hit) ＂ in such clone, identical analytical method and some just come test formula (I) compound to strengthen MSG delicate flavour or known sweetener such as sucrose as analysis tool based on cell and/or based on the analytical method of acceptor, the ability of fructose sweet taste, and be used to provide experimental data to instruct the interactive approach (interative process) of the synthetic and test structure variations of amide compound, it is in conjunction with interim people's taste test that target compound is carried out, thus design, test and identification have concrete material and classification enhancing and required bioactive compound optimum level.
Many embodiments of the present invention relate to the particular compound of formula (I) amide compound and the affirmation of classification, these compounds can be regulated the activity of (strengthen or weaken) T1R1/T1R3 (preferred hT1R1/hT1R3) delicate flavour taste acceptor (umami receptor (umami receptor)), and they separately or can activate the compound of hT1R1/hT1R3 such as MSG with other and unite and play a role.Especially, formula (I) amide compound that can regulate hT1R1/hT1R3 (people's umami receptor) activity in external and/or body is disclosed in a plurality of embodiments of the present invention.On the other hand, the present invention relates to the compound of mediator's delicate flavour (umami) taste perception, when be added to edible or medicinal product or composition in the time, this compound is united separately or with other compound or flavouring and is played a role.
In some embodiments of the present invention, unexpectedly find, at least some formula (I) but amide compound mediator's delicate flavour taste perception, in the time of in being added to edible or medicinal product or composition, this compound is united separately or with other compound or flavouring and is played a role.
External hT1R1/hT1R3 umami receptor activation experiment
In order to discern tasty agents and the flavour enhancer that makes new advances, comprise the compound that identification has delicate flavour activator and reinforcing agent activity (double activity), in the experiment of elementary experiment and secondary, formula (I) compound is screened, comprise that compound dosage replys and strengthen experiment.Elementary experiment in the ability that is used for judging potential adjusting delicate flavour, it has been found that formula (I) amide compound can be used as tasty agents (character that it had originally) or as the flavour reinforcers of MSG, these compounds are discerned, and its active mark provides with the percentage (%) that accounts for maximum MSG intensity.In compound dosage is replied, calculate EC
50Reflect the effectiveness of compound as delicate flavour activator or reinforcing agent.
Use HEK293 clone derivative (referring to, for example: people such as Chandrashekar, Cell (2000) 100:703-711) differentiate compound with delicate flavour characteristic, but this clone stably express G α 15 and hT1R1/hT1R3 (referring to WO 03/001876 A2) under the effect of inducible promoter.
The compound that this document is contained is according to them the activity of hT1R1/hT1R3-HEK293-G α 15 clones to be selected at first.Utilization FLIPR equipment (fluorescence intensity plate reader (FluorometricIntensity Plate Reader), Molecular Devices, Sunnyvale, activity is measured in the automatic fluorescence imaging analysis of carrying out on CA) (being called FLIPR analyzes).To be seeded on the 384-orifice plate (about 48 from clone's cell (called after clone I-17) once, 000 cells/well), the culture medium that described 384-orifice plate comprises contains the Eagle's medium (DMEM of Da Er Becquerel improvement, Dulbecco ' s modified Eagle ' smedium), described culture media supplemented has GlutaMAX (Invitrogen, Carlsbad, CA), 10% dialysis hyclone (Invitrogen, Carlsbad, CA), 100 units/ml benzyl penicillin, 100 μ g/ml streptomysin (Invitrogen, Carlsbad is CA) with 60pM mifepristone (mifepristone) (inducing the expression of hT1R1/hT1R3) (referring to WO03/001876A2).Make the I-17 cell 37 ℃ of growths 48 hours.(OR) (CA) the 4 μ M solution loads in continue 1.5 hours in room temperature to the I-17 cell for Invitrogen, Carlsbad at phosphate buffered saline (PBS) (D-PBS) for Molecular Probes, Eugene with calcium dyestuff Fluo-3AM then.After 25 μ l D-PBS displacement, stimulate by adding 25 μ lD-PBS in FLIPR equipment in room temperature, described D-PBS is supplemented with the different stimulated thing that concentration is the concentration of ultimate density twice.Receptor active is by determining that the maximum fluorescence recruitment quantizes (utilizing the exciting light of 480nm and the emission light of 535nm) after carrying out normalization with respect to the baseline fluorescence intensity of measuring before stimulating.
For dosage-response analysis, the concentration of stimulus is got 10 different values from 1.5nM to 30 μ M, repeats.With respect to replying of producing with the 60mM sodium glutamate activity is carried out normalization, the 60mM sodium glutamate can cause that the acceptor maximum replys.Utilize the nonlinear regression algorithm to measure EC
50(can cause the compound concentration of acceptor 50% activation), wherein the gradient (Hill slope), bottom asymptote (bottom asymptote) and top asymptote can change.(San Dieg when California) dosage-reply data being analyzed, obtains ideal results when utilizing commercial nonlinear regression analysis software of buying such as GraphPad PRISM.
In order to measure the dependence of the related hT1R1/hT1R3 of cell response to the different stimulated thing, selected compounds carries out similarity analysis in the I-17 cell, and these cells are not induced expression of receptor (being called non-I-17 cell of inducing) through mifepristone.This non-I-17 cell of inducing does not demonstrate in FLIPR experiment anyly replys the functional of sodium glutamate or other delicate flavour material.With 10 μ M compounds or concentration is that the compound of 3 times of maximal stimulations adds in the non-umami cells of inducing in the dose response analysis.When using non-umami cells of inducing in FLIPR experiment, the compound that the present invention discloses does not show that any function replys.
Of the present invention aspect some, EC
50Can induce the T1R1/T1R3 activity less than about 10mM explanation compound, such compound is considered to the delicate flavour activator.Preferably, the delicate flavour activator has the EC less than about 1mM
50Value; More preferably, has EC less than about 20 μ M, 15 μ M, 10 μ M, 5 μ M, 3 μ M, 2 μ M, 1 μ M, 0.8 μ M or 0.5 μ M
50Value.
Delicate flavour enhanced activity analysis experiment obtains " EC
50Ratio " measured value, this value can illustrate how amide compound of the present invention strengthens the effect that has existed in the delicate flavour condiment (being generally MSG) in the solution effectively.A series of tests to dose response are carried out in the solution that only contains MSG, once test in conjunction with candidate's formula (I) compound of chosen in advance amount simultaneously with MSG then again.
In this test, under the test compounds existence/non-existent situation of fixed concentration, increase the concentration (from 12 μ M to 81mM) of sodium glutamate, repeat.The concentration of typical test compounds is 30 μ M, 10 μ M, 3 μ M, 1 μ M, 0.3 μ M, 0.1 μ M and 0.03 μ M.The relative effect of formula (I) compound aspect the raising acceptor is by calculating sodium glutamate EC
50The degrees of offset of value is measured.So-called enhancing is defined as ratio (EC
50R), it is at the EC that does not have sodium glutamate under the test compounds situation
50The EC that has sodium glutamate under the situation divided by compound
50The ratio that obtains.If the EC50R of compound〉2.0 then the explanation its be reinforcing agent.
In other words, compare " EC with MSG
50Ratio " based on calculating as giving a definition:
EC with respect to MSG
50Ratio=EC
50(MSG)/EC
50(the MSG+[compound]),
Wherein " [compound] " is meant formula (I) compound concentrations that is used for causing (strengthen or improve) MSG dose response.
It should be noted the EC that records
50Ratio depends on the concentration of compound self to a certain extent.Preferred flavour enhancer has EC high with regard to MSG when employed compound concentration is low
50Ratio.Preferably, measure the EC of delicate flavour humidification
50The ratio experiment is that about 10 μ M carry out between about 0.1 μ M at formula (I) compound concentration, perhaps preferably carries out at 1.0 μ M or 3.0 μ M.
If EC
50Ratio is greater than 1, illustrates that then compound can regulate (raising) hT1R1/hT1R3 activity, and this compound is a flavour enhancer.More preferably, the flavour enhancer compound of described formula (I) has at least 1.2,1.5,2.0,3.0,4.0,5.0,8.0 or 10.0 or higher EC
50Ratio.
In one aspect, particular compound delicate flavour regulating degree is based on it external activation of MSG T1R1/T1R3 is used for estimating.Can predict, can use other known compound that can activate the T1R1/T1R3 acceptor to carry out similar experiment.
Calculate the EC of particular compound and classes of compounds by above-mentioned formula
50Prove that these compounds can regulate hT1R1/hT1R3, in the present invention, embodiment and claims, these compounds are carried out open in detail.
Be used at the method for people's taste test of the umami compound of formula (I) as described below.
Embodiment
Following embodiment is used to illustrate the various exemplary embodiments of the present invention, but is not limited to limit by any way the present invention.
For the purpose that the present invention discloses, the compound that discloses respectively can number acute pyogenic infection of finger tip by embodiment in the following embodiments.For example, described as following embodiment 1, it discloses specific compound (N-(heptan-4-yl) benzo [d] [1,3] dioxole-5-formamide) the experiment analysis results of synthetic and this compound biological effect, wherein this compound can abbreviate compound 1 as.
Embodiment 1
N-(heptan-the 4-yl) benzo [d] [1,3] dioxole-5-formamide
0 ℃, to heptan-4-amine (8.06mL, triethylamine 54mmol) (15.3mL, 108mmol) and dropwise add benzo [1,3] dioxole-5-acyl chlorides (10g, carrene 54mmol) (135mL) solution in carrene (135mL) solution.Reactant mixture is stirred 1h.Removal of solvent under reduced pressure, residue are dissolved among the EtOAc (ethyl acetate).The organic layer 1N HCl aqueous solution, the 1N NaOH aqueous solution, water, salt solution wash in succession, and dry (MgSO4) concentrates then.Residue is recrystallized in EtOAc and hexane, obtains N-(heptan-4-yl) benzo [d] [1, the 3] dioxole-5-formamide (48.3%) of 6.9g white solid.
1H?NMR(500MHz，CDCl
3)：δ0.92(t，6H)，1.38(m，6H)，1.53(m，2H)，4.11(m，1H)，5.63(m，1H)，6.01(s，2H)，7.98(d，1H)，7.27(s，d，2H)。MS(M+H，264)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed on HEK293 clone
50Be 0.2 μ M, and when existing, can strengthen the effectiveness of sodium glutamate, at this moment EC with 0.03 μ M
50Ratio is 6.92.
Embodiment 1-1
The improvement of N-(heptan-4-yl) benzo [d] [1,3] dioxole-5-formamide preparation and purifying:
In clean fume hood, the 3 neck round-bottomed flasks that will be equipped with mechanical agitation assembly, charging hopper, the thermocouple with display, nitrogen air inlet and drying tube place cooling bath.This flask also wraps with nitrogen.In flask, add 674g 4-heptyl amine (1 equivalent, 5.85 moles) under the nitrogen protection.In described flask, add THF (oxolane) (3.37L) then, stirred reaction mixture.Then in nitrogen protection downhill reaction mixture, add triethylamine (1184g, 2 equivalents, 11.7 moles), this reactant mixture is cooled to internal temperature is-5 ℃ to 0 ℃.
In the polyethylene jar, piperonyl acyl chlorides (1080g, 5.85 moles) is dissolved among the THF (3.37L), and under nitrogen protection, stores.This solution is transferred in the charging hopper of 3 neck bottles.Last 1-2 hour, this solution is added in the reactant mixture by part, if desired, utilize external refrigeration to make the internal temperature of reactant mixture remain below 10 ℃.Between reinforced process, the THF solution of this piperonyl acyl chlorides is used nitrogen protection always.After reinforced the finishing, reactant mixture is heated to 20 ℃ to 25 ℃, stirred again 30 minutes.This reaction is monitored with HPLC (high performance liquid chromatography).When reaction is finished (remaining piperonyl acyl chlorides＜1.0%), add methyl-tertbutyl ether (6.73L), stir fast simultaneously, continue 10 minutes.The gained mixture is transferred in the separatory funnel, with 1N HCl (1.7L) washing.Organic layer is used the 100g dried over mgso with 1N NaOH (1.7L), water (3.37L) and salt solution (1.7L) washing.Reactant mixture is concentrated through Buchner funnel filtration and vacuum, and bathing temperature is 35 ℃ to 45 ℃.In gained crude product solid, add heptane (1.76L), stir simultaneously, form thick slurry.Make this dope filtration by Buchner funnel, and with heptane (0.88L) washing once.With solid transfer in the basin of clean drying, 40 ℃ to 45 ℃ vacuum drying, up to constant weight.
The 3 neck round-bottomed flasks that will be equipped with mechanical agitation assembly, condenser, the thermocouple with display, nitrogen air inlet and drying tube place heating jacket.This flask wraps with nitrogen, adding crude product N-under the nitrogen protection (heptan-the 4-yl) benzo [d] [1,3] dioxole-5-formamide (1484g).Add ethyl acetate (3.72L) in addition.It is 50 ℃ to 55 ℃ that reactant mixture is heated to internal temperature.Obtain clear solution.The glass fibre filter of utilization on filter paper with described solution through the Buchner funnel heat filtering.The 3 neck round-bottomed flasks that will be equipped with mechanical agitation assembly, charging hopper, the thermocouple with display, nitrogen air inlet and drying tube place heating jacket.This flask wraps with nitrogen, transfers in this flask above-mentioned filtrate and stirring.Adding thermal reaction mixture is 40 ℃ to 50 ℃ to internal temperature.Last minimum 30 minutes, heptane (9.02L utilizes filter paper to filter through Buchner funnel) is added with stable liquid stream, keeping internal temperature simultaneously is to 40 ℃ to 50 ℃.After adding is finished, reactant mixture is cooled to 0 ℃ to 5 ℃, kept 1 hour in this temperature.Utilize the polypropylene filter pad that gained solution is filtered through Buchner funnel, wash with cold heptane (1.13L utilizes filter paper to filter through Buchner funnel, and is cooled to 0 ℃).Solid transfer is in the basin of clean drying, the shortest dry 14 hours 40 ℃ to 45 ℃ vacuum drying, up to constant.This operation scheme obtains 1276g N-(heptan-4-yl) benzo [d] [1,3] dioxole-5-formamide, and purity is greater than 99.9% (HPLC mensuration), and total recovery is 86%.
Embodiment 1-2
Under the nitrogen protection, in 500mL is equipped with the 3-neck flask of magnetic stirring apparatus, charging hopper, thermocouple, drying tube and cooling bath, add piperonylic acid (25g, 150mmol), CH
2Cl
2(200mL) and DMF (dimethyl formamide) (2.5mL).The gained mixture is cooled to 0 ℃, last about 10 minutes then and add thionyl chloride (18.8g, 158mmol).After adding is finished, this solution is heated to backflow, kept about 1 hour.Reactant mixture is cooled to 0 ℃, and remains on this temperature in order to using subsequently.
Under the nitrogen protection, to 1L be equipped with add in the 3 neck bottles of magnetic stirring apparatus, charging hopper, thermocouple, drying tube and cooling bath the 4-heptyl amine (17.3g, 150mmol), triethylamine (30.5g, 301mmol), CH
2Cl
2(125mL) and DMF (2.5mL).This solution is cooled to 0 ℃, lasts about 1 hour then above-mentioned cold solution of acid chloride is dropwise added, keep temperature to be lower than 10 ℃ simultaneously.After adding is finished, add entry (100mL), make temperature be lower than about 20 ℃ simultaneously.Then the content in the reaction flask is transferred in the separatory funnel, organic layer with 1N HCl (aqueous solution) (2 x 40mL), water (40mL), 1NNaOH (aqueous solution) (40mL), water (40mL) extraction, use NaCl (saturated aqueous solution) (40mL) to extract then.Organic facies MgSO4 drying is filtered, and concentrates volume is reduced, and adds heptane (100mL) afterwards, is concentrated into this solution decompression dried.The gained crude product is handled with heptane (150mL), filters and collects the gained solid, and with heptane (50mL) washing, vacuum drying gets required product then.Yield is 37.4g (94.4%).
Embodiment 2
N-(2-methyl heptan-4-yl) benzo [d] [1,3] dioxole-5-formamide
Adopt and embodiment 1 similar methods, utilize benzo [d] [1,3] dioxole-5-acyl chlorides and 2-methyl heptan-4-amine (embodiment 2a) is prepared.
1H?NMR(500MHz，CDCl
3)：δ?0.93(m，9H)；1.38(m，5H)；1.53(m，1H)；1.66(m，1H)；4.21(m，1H)；5.61(d，1H)；6.01(s，2H)；6.82(d，1H)；7.26(m，2H)。MS(278，M+H)。
The preparation of embodiment 2a:2-methyl heptan-4-amine:
To 2-methyl heptan-4-ketone (4.24g, add in methyl alcohol 33.07mmol) (60mL) solution ammonium acetate (25.50g, 330.71mmol) and sodium cyanoborohydride (2.08g, 33.07mmol).With reactant mixture about 24 hours in stirring at room.Removal of solvent under reduced pressure, residue diluted with water, and, use extracted with diethyl ether with the alkalization of the 15% NaOH aqueous solution.Extract salt water washing through anhydrous magnesium sulfate drying, is filtered, and evaporate to dryness gets 3.3g 2-methyl heptan-4-amine (77%).MS(M+H，130)。
The EC of the hT1R1/hT1R3 umami receptor that the compound activating of embodiment 2 is expressed in HEK293 clone
50Be 0.22 μ M.
Embodiment 3
N-(2-methyl oneself-3-yl) benzo [d] [1,3] dioxole-5-formamide
Adopt and embodiment 1 similar methods, utilize benzo [d] [1,3] dioxole-5-acyl chlorides and 2-methyl oneself-3-amine (embodiment 3a) is prepared.
1H?NMR(500MHz，CDCl
3)：δ?0.93(m，9H)；1.37(m，3H)；1.56(m，1H)；1.83(m，1H)；4.01(m，1H)；5.67(d，1H)；6.02(s，2H)；6.82(d，1H)；7.28(m，2H)。MS(M+H，264)。
Embodiment 3a: adopt the same steps as of describing with embodiment 2a, with the 2-methyl oneself-3-ketone be initiation material prepare the 2-methyl oneself-3-amine.Yield: 40%.
1H?NMR(500MHz，CDCl
3)：δ?0.86(d，3H)；0.91(m，6H)；1.20-1.29(m，2H)；1.38-1.47(m，2H)；1.47(s，2H)；1.58(m，1H)；2.51(m，1H)。MS(M+H.116)。
The EC of the hT1R1/hT1R3 umami receptor that the compound activating of embodiment 3 is expressed in HEK293 clone
50Be 0.61 μ M.
Embodiment 4
N-(2, the 3-dimethyl cyclohexane) benzo [d] [1,3] dioxole-5-formamide
With 2,3-dimethyl cyclohexyl amine (20 μ mol) and benzo [d] [1,3] dioxole-5-carboxylic acid (1.1 equivalent) be dissolved in respectively acetonitrile/carrene (200 μ L, 2:1) in.PS-carbodiimide resin (2 equivalent) is loaded in the Greiner plate of 1.2mL96 hole, add amine and acid solution then.Hydroxybenzotriazole (1.1 equivalent) is dissolved among the DMF (100mL), is added in the reacting hole then.Room temperature oscillating reactions mixture overnight.In case reaction is finished, just in reactant mixture, add PS-three polyimide resins (PS-Trisamineresin) (1.5 equivalent), make gained solution room temperature shaken overnight.(200mL) is added in the reacting hole with acetonitrile, and the top clear solution is transferred in the new plate.This solution evaporate to dryness is got N-(2, the 3-Dimethylcyclohexyl) benzo [d] [1,3] dioxole-5-formamide.MS(M+H，276.20)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.45 μ M, and when existing, can strengthen the effectiveness of sodium glutamate, at this moment EC with 1 μ M
50Ratio is 8.4.
Embodiment 5
(R)-2-(benzo [d] [1,3] dioxole-6-formamido group)-4-methylvaleric acid methyl esters
Adopt and embodiment 1 similar methods, utilize benzo [d] [1,3] dioxole-5-acyl chlorides and D-leucine methyl ester hydrochloride to be prepared.Yield: 83%.
1H?NMR(500MHz，CDCl
3)：δ?0.98(m，6H)；1.63-1.67(m，1H)；1.71-1.76(m，2H)；3.76(s，3H)；4.83(m，1H)；6.03(s，2H)；6.38(d，1H)；6.83(d，1H)；7.32(s，1H)；7.33(d，1H)。MS(M+H，294)。m.p：89-90℃。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.34 μ M, and when existing, can strengthen the effectiveness of sodium glutamate, at this moment EC with 0.1 μ M
50Ratio is 4.9.
Embodiment 6
(R)-2-(benzo [d] [1,3] dioxole-6-formamido group)-3 Methylbutanoic acid methyl esters
Adopt and embodiment 4 similar methods, utilize benzo [d] [1,3] dioxole-5-carboxylic acid and (R)-2-amino-3 Methylbutanoic acid methyl esters to be prepared.Yield: 50%.MS(M+H；280.1)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 1.16 μ M.
Embodiment 7
N-(oneself-the 3-yl)-4-methoxyl group-3-methyl benzamide
Adopt and embodiment 4 similar methods, utilize 4-methoxyl group-3-methyl benzoic acid and own-3-amine (embodiment 28a) to be prepared.
1H?NMR(500MHz，CDCl
3)：δ?0.94(m，6H)；1.41(m，4H)；1.46(m，1H)；1.64(m，1H)；2.24(s，3H)；3.87(s，3H)；4.08(m，1H)；5.69(d，1H)；6.83(d，1H)；7.54(s，1H)；7.62(d，1H)。MS(M+H，250)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.12 μ M.
Embodiment 8
N-(heptan-the 4-yl)-6-methyl benzo [d] [1,3] dioxole-5-formamide
Adopt and embodiment 4 similar methods, utilize 6-methyl benzo [d] [1,3] dioxole-5-carboxylic acid and heptan-4-amine is prepared.MS(M+H，278.67)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.11 μ M.
Embodiment 9
N-(heptan-the 4-yl)-2-methyl benzo [d] [1,3] dioxole-5-formamide
With N-(heptan-4-yl)-3,4-dihydroxy benzoyl amine (0.5mmol) is dissolved in the toluene (1.6mL).P-methyl benzenesulfonic acid monohydrate (0.3 equivalent) is added in the reactant mixture, adds acetaldehyde (2 equivalent) then.Reactant mixture utilizes microwave (180 ℃ 300W) are handled lasting 10 minutes.With the solvent evaporate to dryness.Residue is dissolved in the methyl alcohol (1ML), through the HPLC purifying.Productive rate 20%, MS (M+H 278.10).
A. adopt with embodiment 4 similar methods and utilize 3, the 4-dihydroxy-benzoic acid and heptan-4-amine prepares N-(heptan-4-yl)-3,4-dihydroxy benzoyl amine.Yield: 25%.MS(M+H，252.1)。
The EC of the hT1R1/hT1R3 umami receptor that the compound activating of embodiment 9 is expressed in HEK293 clone
50Be 0.1 μ M, and when existing, can strengthen the effectiveness of sodium glutamate, at this moment EC with 0.03 μ M
50Ratio is 3.68.
Embodiment 10
N-(heptan-the 4-yl)-2,2-dimethylbiphenyl [d] [1,3] dioxole-5-formamide
Adopt and embodiment 4 similar methods, utilize 2,2-dimethylbiphenyl [d] [1,3] dioxole-5-carboxylic acid sodium and 4-heptyl amine (embodiment 10a) are prepared.Yield 30%.
1H?NMR：0.92(t，6H，J＝7.2Hz)，1.42(m，6H)，1.53(m，2H)，1.68(s，6H)，4.12(m，1H)，5.61(d，1H，J＝8.9Hz)，6.72(d，1H，J＝8Hz)，7.16(d，1H，J＝1.5Hz)，7.22(dd，1H，J＝1.5Hz，J＝17Hz)。MS(M+H，292)。
A.2,2-dimethylbiphenyl [d] [1,3] dioxole-5-carboxylic acid sodium and 4-heptyl amine:
Under the room temperature, with 2, (461mg 2.08mmol) stirred 20 hours in the Zai diox (16mL) and the 1.0N NaOH aqueous solution (4.16mL) 2-dimethylbiphenyl [d] [1,3] dioxole-5-carboxylic acid, ethyl ester (embodiment 10b).Solvent decompression removed obtain required product (449mg).(M-H，193)。
B.2,2-dimethylbiphenyl [d] [1,3] dioxole-5-carboxylic acid, ethyl ester:
With 3, the 4-dihydric ethyl benzoate (910.9mg, 5mmol) with 2, the 2-dimethoxy propane (1.23mL, 10mmol) and the p-methyl benzenesulfonic acid of catalytic amount in toluene, mix.Utilize Dean-Stark trap (Dean-Stark trap) that the gained mixture was added hot reflux 20 hours.After the removal of solvent under reduced pressure, in ethyl acetate, saturated aqueous solution, water and the salt solution with sodium acid carbonate washs successively then with dissolving crude product.Organic layer is through anhydrous sodium sulfate drying.Adopt silica gel column chromatography to utilize hexane: ethyl acetate gradient: 90:10 to 75:25 carries out purifying, gets white powder (539.1mg, 49%).
1H?NMR(CDCl
3)：1.36(t，3H，J＝7.2Hz)，1.69(s，6H)，4.32(q，2H，J＝7.1Hz，J＝14.2Hz)，6.74(d，1H，d，J＝8.2Hz)，7.38(d，1H，J＝1.7Hz)，7.61(dd，1H，J＝1.8Hz，J＝8.3Hz)。
The EC of the hT1R1/hT1R3 umami receptor that the compound activating of embodiment 10 is expressed in HEK293 clone
50Be 2.7 μ M.
Embodiment 11
2,3-dihydro-benzo [1,4] bioxin-6-carboxylic acid (1-propyl group-butyl)-acid amides
Adopt and embodiment 4 similar methods, utilize 2,3-dihydro-benzo [1,4] bioxin-6-carboxylic acid and heptan-4-amine is prepared.MS(M+H，278.2)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.49 μ M.
Embodiment 12
(R)-preparation of 4-methyl-2-(5-chlorobenzene and furans-2-formamido group) methyl valerate
Adopt and embodiment 4 similar methods, utilize 5-chlorobenzene and furans-2-carboxylic acid and D-leucine methyl ester to be prepared.MS(M+H，324)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.82 μ M.
Embodiment 13
N-(heptan-the 4-yl) benzo [b] thiophene-2-carboxamide derivatives
Adopt and embodiment 4 similar methods, utilize benzo [b] thiophene-2-carboxylic acid and 4-heptyl amine to be prepared.MS(M+H，276)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.21 μ M.
Embodiment 14
4-methyl-3-methyl mercapto-N-(1-propyl group butyl) benzamide
Adopt and embodiment 4 similar methods, utilize 4-methyl-3-(methyl sulfenyl) benzoic acid (embodiment 14a) and 4-heptyl amine to be prepared.Yield: 50%.
1H?NMR(500MHz，CDCl
3)：δ?0.93(t，6H，J＝7.2Hz)，1.40-1.41(m，8H)，2.35(s，3H)，2.51(s，1H)，4.15(m，1H)，5.75(d，1H，J＝8.5Hz)，7.15(d，1H，J＝7.8Hz)，7.31(d，1H，J＝7.8Hz)，7.65(d，1H，J＝1.5Hz)。MS(M+H，280)。
A.4-methyl-3-(methyl sulfenyl) benzoic acid: 3-amino-4-methyl benzoic acid is suspended in the frozen water (55mL), slowly adds dense HCl (8.56mL).Last 15 fens and add sodium nitrite in aqueous solution (2.4g is in 5.5mL) in the clockwise suspension, the gained mixture was stirred 15 minutes again.Then, dropwise add sodium acetate aqueous solution (9.31g is in 18mL).Reaction was carried out 45 minutes.Obtain dark crocus sediment.Sediment is filtered out and wash with several portions of frozen water.250mL aqueous solution with solid and potassium xanthate (11.93g) and potash (8.22g).Reaction vessel is placed oil bath, and oil bath is heated to 70 ℃ in advance, and the gained mixture was stirred 25 minutes.Gained pale red solution is taken out from oil bath, and stirred again 15 minutes, reach 30 ℃ up to temperature.Add NaOH (0.782g), stir and make it dissolving.Add dimethyl suflfate (5.70mL).With mixture stirring at room 1 hour, briefly reflux then.Removal of solvent under reduced pressure obtains the crocus solid.With the H of this solid with 2.0N
2SO
4Solution-treated, and extract with EtOAc.Extract washes with water, then through anhydrous MgSO
4Dry.Removal of solvent under reduced pressure gets pale red crude product solid.This solid absorption on silica gel and with column chromatography purification (gradient is the hexane solution of 5 to 50% ethyl acetate), is obtained 4-methyl-3-(methyl sulfenyl) benzoic acid, be buff powder (2g).
1H?NMR(500MHz，CDCl
3)：δ?2.39(s，3H)，2.54(s，3H)，7.24(d，1H，J＝7.8Hz)，7.79(d，1H，J＝7.8Hz)，7.86(d，1H，J＝1.5Hz)。
The EC of the hT1R1/hT1R3 umami receptor that the compound activating of embodiment 14 is expressed in HEK293 clone
50Be 0.21 μ M.
Embodiment 15
4-methoxyl group-3-methyl-N-(2-methyl heptan-4-yl) benzamide
Adopt the method similar methods of describing with embodiment 4, utilize 4-methoxyl group-3-methyl benzoic acid and 2-methyl-4-heptyl amice (embodiment 2a) to be prepared.Productive rate: 45%.
1HNMR(500MHz，CDCl
3)：δ?0.93(m，9H)；1.39(m，5H)；1.53(m，1H)；1.67(m，1H)；2.24(s，3H)；3.86(s，3H)；4.23(m，1H)；5.64(d，1H)；6.82(d，1H)；7.54(s，1H)；7.61(d，1H)。MS(278，M+H)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.1 μ M.
Embodiment 16
(R)-2-(3-chloro-4-methoxybenzoyl amino)-4-methylvaleric acid methyl esters
Adopt and embodiment 4 similar methods, utilize 3-chloro-4-methoxy benzoic acid and D-leucine methyl ester hydrochloride to be prepared.MS(M+H，314.10)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.08 μ M, and when existing, can strengthen the effectiveness of sodium glutamate, at this moment EC with 0.01 μ M
50Ratio is 13.18.
Embodiment 17
3,4-dimethoxy-N-(1-propyl group-butyl)-benzamide
Adopt and embodiment 4 similar methods, utilize 3, the 4-dimethoxybenzoic acid and heptan-4-amine is prepared.MS(M+H，279.37)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.36 μ M.
Embodiment 18
(R)-and N-(1-methoxyl group-4-methylpent-2-yl)-3, the 4-dimethyl benzamide
To (R)-N-(1-hydroxy-4-methyl penta-2-yl)-3, (1.59g, (281mg, 7mmol) powder stir this solution 2 hours at 0 ℃ the 4-dimethyl benzamide 6.39mmol) to add NaOH in dry DMF (20mL) solution of (embodiment 18a).Last 1 hour and dropwise add iodomethane (1 equivalent, DMF 6.39mmol) (10ml) solution.Temperature maintenance is at 0 ℃, and the gained mixture was stirred 1 hour.Add 300ml water and will react cancellation.The water layer dichloromethane extraction is through MgSO
4Dry also evaporate to dryness.Residue is through flash chromatography on silica gel purifying (toluene-ethyl acetate; The 5-20% gradient) gets 1.23g (R)-N-(1-methoxyl group-4-methylpent-2-yl)-3,4-dimethyl benzamide (73%).
1HNMR(500MHz，CDCl
3)：δ?0.94-0.97(t，6H)，1.41-1.47(M，1H)，1.54-1.60(m，1H)，1.64-1.68(m，1H)，2.29(d，6H)53.36(s3?3H)，3.45-3.50(m，2H)，4.34-4.39(m，1H)，6.23-6.25(d，1H)，7.16-7.17(d，1H)，7.47-7.49(dd，1H)，7.56(s，1H)。MS(M+H，264.3)。
A. adopt and embodiment 4 similar methods, utilize 3,4-mesitylenic acid and (R)-amino leucinol, preparation (R)-N-(1-hydroxy-4-methyl penta-2-yl)-3,4-dimethyl benzene carbon amide.Productive rate: 75%.MS(M+H，250.3)。
The EC of the hT1R1/hT1R3 umami receptor that the compound activating of embodiment 18 is expressed in HEK293 clone
50Be 0.2 μ M.
Embodiment 19
(R)-2-(2,3-dimethyl furan-5-formamido group)-4-methylvaleric acid methyl esters
Adopt and embodiment 4 similar methods, utilize 4,5-dimethyl-furans-2-carboxylic acid and D-leucine methyl ester are prepared.Yield: 27%.
1H NMR (500MHz, CDCl
3): δ 0.96 (t, 6H), 1.66 (m, 3H), 1.96 (s, 3H), 2.26 (s, 3H), 3.75 (s, 3H), 4.78 (m, 1H), 6.51 (d, 1H), 6.89 (s, 1H).MS(M+H，268)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.59 μ M.
Embodiment 20
(R)-2-(2, the different nicotinoyl amino of 6-dimethoxy)-4-methylvaleric acid methyl esters
Adopt and embodiment 4 similar methods, utilize 2,6-dimethoxy-isonicotinic acid and D-leucine methyl ester are prepared.
1H NMR (500MHz, CDCl
3): δ 0.92 (d, 3H, J=7.27Hz), 0.93 (d, 3H, J=7.26Hz), 1.41-1.58 (m, 8H), 3.95 (s, 3H), 4.08 (s, 3H), 4.15 (m, 1H), 6.43 (d, 1H, J=8.32Hz), 7.47 (m, broad peak, 1H), 8.41 (d, 1H, J=8.34Hz).MS(M+H；311)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 1.91 μ M.
Embodiment 21
(S)-N-(2,3-dihydro-1H-indenes-1-yl)-4-methoxyl group-3-methyl benzamide
Adopt and embodiment 4 similar methods, utilize 4-methoxyl group-3-methyl benzoic acid and (S)-2,3-dihydro-1H-indenes-1-amine is prepared.Yield 63%.
1HNMR(500MHz，DMSO)：δ?1.94-1.99(m，1H)，2.17(s，3H)，2.41-2.46(m，1H)，2.82-2.87(m，1H)，2.96-3.01(m，1H)，3.83(s，3H)，5.53-5.57(dd，1H)，6.98-6.99(d，1H)，7.16-7.23(m，3H)，7.26-7.27(m，1H)，7.75-7.80(m，2H)，8.54-8.55(d，1H)。MS(M+H，282)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.08 μ M.
Embodiment 22
(R/S)-4-methoxyl group-N-(5-methoxyl group-2,3-dihydro-1H-indenes-1-yl)-3-methyl benzamide
Adopt and embodiment 4 similar methods, utilize 4-methoxyl group-3-methyl benzoic acid and 5-methoxyl group-2,3-dihydro-1H-indenes-1-amine (embodiment 22-2a) is prepared (47%).MS(M+H，312)。
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.08 μ M.
Embodiment 22-2a:5-methoxyl group-2,3-dihydro-1H-indenes-1-amine
With 5-methoxyl group-2, (1g, (730mg is in 10ml aqueous solution 10.5mmol) 6.17mmol) to be added to hydroxylamine hydrochloride for 3-dihydro 1-Indanone.The gained mixture is warmed to 70 ℃, and (1.4g is 16.7mmol) at 7mL H to add sodium acetate
2Solution among O, 14ml MeOH, the 3ml THF.After 1.5 hours, add 10ml H 70 ℃ of stirrings
2O produces sediment, and suspension was stirred 2 hours again.Filter the collecting precipitation thing and get almost quantitative 5-methoxyl group-2,3-dihydro 1-Indanone oxime, this compound is directly used in next step without being further purified.With described oxime (0.5g 2.82mmol) is dissolved among the MeOH, add the Raney Ni of catalytic amount and the methanol solution of ammonia (25mL, 7N).Reactant mixture stirred under hydrogen in room temperature spend the night.The gained slurries are through diatomite filtration, and vacuum concentrates, and with the EtOAc dilution, water and salt water washing are through MgSO
4Drying is filtered, vacuum concentrate the crude product (yield 45%) of title amine compound.Described crude product amine is without being further purified direct use.
Also synthesized numerous formulas (I) amide compound that drops in other local ＂ oxamides ＂ compound subclass scope that discloses of the present invention, and they have been carried out experiment test as the effectiveness of the activator of the hT1R1/hT1R3 umami receptor of expressing in HEK293 clone.
Embodiment 23
The general step A of preparation oxamides
Synthesizing of N-(2-methoxyl group-benzyl)-N '-(2-pyridine-2-base-ethyl)-oxamides
2-methoxybenzylamine (5mmol) is mixed in no Shui diox with triethylamine (2 equivalent).Add ethyl oxalate acyl chlorides (1 equivalent), the gained mixture was room temperature vibration 0.5-2 hour.Add 2-(2-pyridine radicals) ethylamine (1 equivalent) then, gained suspension is 80 ℃ of heated overnight.With the gained solution concentration, residue is dissolved in the ethyl acetate, and washes with water.Organic layer is through dried over sodium sulfate, and evaporate to dryness gets crude product, and this crude product obtains title compound through purification by flash chromatography.Yield 70%, m.p.118-119 ℃; M/e=314[M+1]; 1H NMR (CDCl3): 3.02 (t, 2H), 3.76 (dt, 2H), 3.86 (s, 3H), 4.47 (d, 2H), 6.80-6.90 (m, 2H), 7.14-7.18 (m, 2H), 7.20-7.30 (m, 2H), 7.55-7.62 (m, 1H), 7.75-7.83 (m, 1H), 8.05-8.12 (m, 1H), and 8.55-8.63 (m, 1H).
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.34 μ M, and when existing, can strengthen the effectiveness of sodium glutamate, at this moment EC with 0.3 μ M
50Ratio is 18.85.
Embodiment 24
N-(2,4-dimethoxy-benzyl)-N '-(2-pyridine-2-base-ethyl)-oxamides
Adopt and embodiment 23 similar methods, utilize 2,4-dimethoxybenzylamine, ethyl oxalate acyl chlorides and 2-(2-pyridine radicals) ethylamine is prepared.Yield 72%, m.p.123-124 ℃; M/e=344[M+1];
1H NMR (CDCl3): δ 3.02 (t, 2H); 3.73 (dd, 2H); 3.78 (s, 3H); 3.82 (s, 3H); 4.38 (d, 2H); 6.40 (dd, 1H); 6.44 (d, 1H); 7.14 (m, 3H); 7.59 (m, 1H); 7.82 (t, 1H); 8.11 (t, 1H); 8.56 (d, 1H);
13C NMR: δ 36.9,38.9,39.4,55.6, and 55.6,98.8,104.1,117.8,121.9,123.5,130.7,136.8,149.6,158.8,158.8,159.6,160.1,161.0.
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.09 μ M, and when existing, can strengthen the effectiveness of sodium glutamate, at this moment EC with 0.3 μ M
50Ratio is 6.51.
Embodiment 24-1
Improvement to N-(2,4-dimethoxy-benzyl)-N '-(2-pyridine-2-base-ethyl)-oxamides preparation and purifying:
The reactor of clean and dry band sheath is equipped with condenser, Clarkson joint (Claisenadapter), temp probe and charging hopper or column cap (head column).With this reactor with nitrogen wash at least 15 minutes.In reactor, add 1396g (1 equivalent, 8.3mol) 2,4-dimethoxybenzylamine, 1,693g (2 equivalents, 16.7mol) triethylamine and 25,086mL THF then.Described mixture is cooled to 0 to 5 ℃.(1140g, 1 equivalent 8.3mol) is added in charging hopper or the column cap and so that internal temperature is no more than 10 ℃ speed is added in the reactant with chlorine oxo ethyl acetate.Begin to form solid after adding about 1/3.After adding is finished, stop cooling, stirred the gained slurries 30 minutes at 5 ℃ to 15 ℃.When finishing, reactant mixture is warmed to 20 ℃ to 25 ℃.Organic facies is with 22, and 580mL 1N HCl washed twice uses 12 then, the washing of 600mL saturated sodium bicarbonate.Then with 12, the water washing of 463mL salt is through dried over mgso.The gained mixture filters through thin Celite pad, 40 ℃ to 45 ℃ concentrate yellow oil.It is 2 that separation obtains total amount, the crude product N-of 052g (7.7mol, 92%) (2,4-dimethoxy-benzyl)-oxalic acid acid amides ethyl ester.
In clean fume hood, the 3 neck round-bottomed flasks that will be equipped with mechanical agitation assembly, charging hopper, the thermocouple that has display, nitrogen air inlet and drying tube place heating jacket.Flask is wrapped with nitrogen.Under nitrogen protection, N-(2,4-dimethoxy-benzyl)-oxalic acid acid amides ethyl ester (1116g, 1 equivalent, 4.18 moles), acetonitrile (12.5L) and 2-(2-pyridine radicals)-ethamine (1 equivalent, 4.18 moles) are added in the flask.With the gained vlil, and kept this temperature at least 20 hours (81 ℃).After reaction is finished, transfer to reactant mixture in the cold bath and be cooled to 65 ℃.Then gained solution is transferred in the round-bottomed flask, vacuum concentrates, and bath temperature is 40 ℃ to 45 ℃.Residue is dissolved among the 1NHCl (16L x 2 separatory funnels), and transfers in the separatory funnel with isopropyl acetate extraction (13.95Lx 2 separatory funnels).Merge organic layer, with 1N HCl (13.61L x 2 separatory funnels) extraction.Combining water layer washs and transfers in the 3 neck round-bottomed flasks of the thermocouple that is equipped with mechanical agitation assembly, charging hopper and has display with isopropyl acetate (3.4L x 2 separatory funnels), and this flask places cooling bath.In flask, add 6N NaOH by charging hopper, make reactant mixture maintain 20 ℃ to 30 ℃.Add carrene and make gained slurries (9.82L) dissolving, the gained clear solution is transferred in the separatory funnel.Collect organic facies, with the NaOH aqueous solution (6.88L) washing, through K
2CO
3Drying utilizes the polypropylene filter cloth to filter by Buchner funnel.Gained solution is transferred in the round-bottomed flask, and vacuum concentrates, and bathing temperature is 35 ℃ to 40 ℃.With the gained solid transfer in the basin of clean drying, 40 ℃ to 45 ℃ vacuum drying up to constant weight.
The 3 neck round-bottomed flasks that will be equipped with mechanical agitation assembly, condenser, the thermocouple that has display, nitrogen air inlet and drying tube place heating jacket.Flask is wrapped with nitrogen.Nitrogen protection adds 1317g crude product N-(2,4-dimethoxy-benzyl)-N '-(2-pyridine-2-base-ethyl)-oxamides down, adds 18.7L ethyl acetate then.With reactant mixture be heated to internal temperature be 50 ℃ to 55 ℃ up to obtaining clear solution.Remove heating, add heptane with stable liquid stream by charging hopper.After adding is finished, reactant mixture is placed ice bath, be cooled to 20 ℃ to 25 ℃, remained on this temperature at least 30 minutes.Utilize polypropylene filter spare to filter the gained material by Buchner funnel, and it is transferred in the 2:3 mixture (7L) of heptane-ethyl acetate.The gained slurries were stirred 30 minutes, utilize polypropylene filter spare to filter by Buchner funnel.The 2:3 mixture of gained solid with 800mL heptane-ethyl acetate cleaned and drying.Repeat this recrystallization washing step and obtain 1079g end product (yield 63%), measure purity greater than 99.5% through HPLC.Can be recrystallized again if desired so that purity more than or equal to 99.5%.In these situations, described material is with the ethyl acetate of 8:2: heptane is recrystallized, and the method for employing is similar to said method, thereby preparation purity is greater than 99.5% product.
This recrystallization method can be used for other oxamides analog that purifying the present invention discloses.
Embodiment 24-2
The improvement of N-(2,4-dimethoxy-benzyl)-N '-(2-pyridine-2-base-ethyl)-oxamides preparation and purifying
12L in immersing cooling bath is equipped with in the 3-neck round-bottomed flask that mechanical agitator, thermocouple, charging hopper, drying tube and nitrogen wraps and adds 2, and 4-dimethoxybenzylamine hydrochloride (500g, 2.45mol) and toluene (6L).(1027mL 7.36mol), stirs gained solution 1 hour in environment temperature, then reaction vessel is placed methyl alcohol/ice bath, and gained solution is cooled to 0 ℃ slowly to add triethylamine.(273mL 2.45mol), keeps reaction temperature to be lower than about 10 ℃ simultaneously to last about 25 minutes adding 2-chloro-2-oxo ethyl acetate.Reaction solution is warming to 22 ℃ then, stirs in environment temperature and spend the night.Course of reaction is through gas-chromatography monitoring (get an aliquot reaction solution, make it pass through filtration syringe, the 1:1 mixture with TEA/THF cleans this salt then).When 2, the amount of 4-dimethoxybenzylamine can judge that less than 1% o'clock reaction is complete.
In case judge to react completely, solution is cooled to 15 ℃ again, add 1N HCl (aqueous solution) (3L), adding speed is to make its temperature be no more than about 23 ℃.Transfer in the polyethylene jar reaction solution and pulp in toluene (2.5 to 4mL/g initiation material), filter and collect, filtrate sets aside.With solid pulp in toluene (2.5 to 4mL/g initiation material) again, filter once more and collect liquid filtrate.
Merging filtrate is also transferred to it in separatory funnel, and organic facies is drained.Solid is used O for toluene once more, and organic layer is drained.Merge organic layer, with 1N HCl (aqueous solution) (2 x 2L), NaHCO
3(saturated aqueous solution) (2 x 2L), NaCl (saturated aqueous solution) (2L) wash, through MgSO
4Drying is filtered.Under the nitrogen protection, the filtrate 12L that packs into is equipped with in the 3-neck round-bottomed flask of mechanical agitator, thermocouple, charging hopper, drying tube and heating jacket.Slowly add 2-(2-amino-ethyl) pyridine (292mL), keeping temperature is 15 ℃ to 25 ℃.After adding is finished, reactant mixture is added hot reflux spend the night.Then reaction vessel is cooled to about 35 ℃, adds methyl tertiary butyl ether(MTBE) (6.3L), the gained mixture is cooled to about 20 ℃, product begins precipitation afterwards.Described solution was kept 4 hours at 10 ℃, kept again 30 minutes at 0 ℃ to 5 ℃ then.Filter to collect product, with heptane (4 x 6L) wash the 610g crude product.The 12L that under the nitrogen protection crude product packed into is equipped with in the 3-neck round-bottomed flask of mechanical agitator, thermocouple, charging hopper, drying tube and heating jacket.Add ethyl acetate (9.15L, 15mL/g crude product material), gained solution is heated up to obtaining clear solution.Add extra heptane (6.71mL), the gained slurries are cooled to about 20 ℃, stirred again 30 minutes.Filter and collect the gained solid, and then pulp in heptane/ethyl acetate (2:3) mixture (6.1L).Solid collected by filtration once more, filter cake is with heptane/ethyl acetate (370mL) washing.The product drying of collecting is to constant weight.Output is 356g (42%).
Embodiment 25
Synthetic oxamides is the general step B of N-(4-methyl-benzyl)-N '-(2-pyridine-2-base-ethyl)-oxamides
Make 4-methylbenzylamine (1mmol) and ethyl oxalate acyl chlorides (1 equivalent) in acetonitrile in the presence of triethylamine (2 equivalent) at room temperature reaction 0.5-1 hour.Add 2-(2-pyridine radicals) ethylamine (1 equivalent) then, suspension was heated 5 minutes at 160 ℃ in microwave reactor.The gained reactant mixture gets pure title oxamides compound behind preparation property HPLC.Productive rate 60%; M.p.152-154 ℃; M/e=298[M+1];
1H NMR (CDCl
3): δ 2.33 (s, 3H), 3.10 (t, 2H), 3.75 (dt, 2H), 4.43 (d, 2H), 7.10-7.15 (m, 4H), 7.18-7.22 (m, 2H), 7.65-7.73 (m, 2H), 8.12 (b, 1H), 8.60 (d, 1H).
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.41 μ M.
Embodiment 26
N-(2-methoxyl group-4-methyl-benzyl)-N '-(2-(pyridine-2-yl) ethyl) oxamides
Adopt and embodiment 25 similar methods, utilize (2-methoxyl group-4-aminomethyl phenyl) methylamine (embodiment 132a), ethyl oxalate acyl chlorides and 2-(2-pyridine radicals) ethylamine to be prepared, productive rate is 20%.m.p：128-131℃；m/e＝328[M+1]；
1H?NMR(CDCl
3)：2.33(s，3H)；3.02(t，2H)；3.73(m，2H)；3.84(s，3H)；4.42(d，2H)；6.70(m，2H)；7.14(m，3H)；7.60(m，1H)；7.86(s，1H)；8.09(s，1H)；8.56(d，1H)。
A. (2-methoxyl group-4-aminomethyl phenyl) methylamine: (200mg slowly adds 1MBH in THF 1.21mmol) (0.5mL) solution to 2-methoxyl group-4-methyl benzamide (embodiment 132b) in room temperature
3THF (2.4ml, 2.42mmol).The gained mixture was heated 7 minutes at 130 ℃ in microwave reactor.Dropwise add the 6N HCl aqueous solution (1mL) in room temperature then.The gained mixture heated 4 minutes at 120 ℃ in microwave reactor.With gained reactant mixture Et
2O (ether) (3 x 3mL) washing is cooled to 0 ℃ then, adds the 10N NaOH aqueous solution (0.8mL).Obtained aqueous solution K
2CO
3Saturated.Product CHCl
3(6 x 5mL) extraction.Dry organic extract liquid (1:1 K
2CO
3/ Na
2SO
4), filter, vacuum concentrate 180mg (2-methoxyl group-4-aminomethyl phenyl) methylamine, this product directly uses.
B.2-methoxyl group-4-methyl benzamide: 2-methoxyl group-4-methyl benzoic acid (500mg, 3.01mmol) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (577mg, 3.01mmol) and I-hydroxybenzotriazole (407mg, 3.01mmol) in the 25ml carrene in mixed at room temperature, stirred 5 minutes.(4.5ml, 9.03mmol), reactant mixture about 5 hours in stirring at room is then with the carrene dilution, with 1N HCl, saturated NaHCO for the methanol solution of adding 2M ammonia
3, water and salt water washing, through MgSO
4Drying, filter evaporate 440mg 2-methoxyl group-4-methyl benzamide, yield is 88%.
The EC of the hT1R1/hT1R3 umami receptor that the compound activating of embodiment 26 is expressed in HEK293 clone
50Be 0.04 μ M.
Embodiment 27
N-(2, the 4-dimethyl benzyl)-N '-(2-(pyridine-2-yl) ethyl) oxamides
Adopt and embodiment 25 similar methods, utilize (2, the 4-3,5-dimethylphenyl) methylamines (embodiment 133a), ethyl oxalate acyl chlorides and 2-(2-pyridine radicals) ethylamine to be prepared, yield is 60%; M.p.148-149 ℃; M/e=312[M+1];
1H NMR (CDCl
3): 2.28 (s, 3H); 2.30 (s, 3H); 3.05 (t, 2H); 3.76 (dd, 2H); 4.43 (d, 2H); 6.99 (m, 2H); 7.11 (d, 1H); 7.17 (m, 2H); 7.54 (s, 1H); 7.62 (m, 1H); 8.17 (s, 1H); 8.58 (d, 1H).
A. (2, the 4-3,5-dimethylphenyl) methylamine: (15.2ml 15.2mmol) places pre-dry flask with the 1M THF solution of lithium aluminium hydride reduction under 0 ℃ and argon shield; With 2, (1.0g, 15ml anhydrous ether solution 7.6mmol) dropwise adds 4-dimethyl benzene formonitrile HCN.After the adding, reactant mixture slowly is warming to room temperature, stirred 3 hours.Be cooled to 0 ℃ then, add anhydrous sodium sulfate, dropwise add 1ml water.The gained mixture is diluted with ethyl acetate, remove by filter insoluble matter, filtrate water and salt water washing are through MgSO
4Drying is filtered, evaporate to dryness, and the 1.03g that obtains quantitative yield pure (2, the 4-3,5-dimethylphenyl) methylamine does not need purifying.
The EC of the hT1R1/hT1R3 umami receptor that the compound activating of embodiment 27 is expressed in HEK293 clone
50Be 0.07 μ M.
Embodiment 28
N-(4-ethyoxyl-2-methoxy-benzyl)-N '-(2-(pyridine-2-yl) ethyl) oxamides
Adopt and embodiment 25 similar methods, utilize (4-ethyoxyl-2-methoxyphenyl) methylamine (embodiment 134a), ethyl oxalate acyl chlorides and 2-(2-pyridine radicals) ethylamine to be prepared; Yield 10%; M.p.117-118 ℃; M/e=358[M+1];
1H NMR (CDCl
3): 1.40 (t, 3H); 3.03 (t, 2H); 3.74 (dd, 2H); 3.82 (s, 3H); 4.01 (dd, 2H); 4.39 (d, 2H); 6.39 (d, 1H); 6.44 (s, 1H); 7.15 (m, 3H), 7.61 (m, 1H); 7.81 (s, 1H); 8.10 (s, 1H); 8.56 (d, 1H).
A. (4-ethyoxyl-2-methoxyphenyl) methylamine: to 4-ethyoxyl-2-methoxybenzaldehyde (embodiment 134b) (880mg, 4.88mmol) the 50ml absolute methanol solution in add ammonium acetate (7.5g, 97.60mmol) and sodium cyanoborohydride (613mg, 9.76mmol).With gained reactant mixture about 4 hours in stirring at room, concentrate through Rotary Evaporators then, residue diluted with water alkalizes with the 15% NaOH aqueous solution, uses ethyl acetate extraction, and water and salt water washing are through MgSO
4Drying is filtered, solvent evaporated, and residue gets the 150mg product through silica gel column chromatography (DCM/MeOH:9:1); Yield is 17% (this method is not through optimizing).
B.4-ethyoxyl-2-methoxybenzaldehyde: to 4-hydroxyl-2-methoxybenzaldehyde (1.0g, 6.57mmol) the 10ml acetone soln in add potash (0.91g, 6.57mmol) and iodoethane (1.6ml, 19.71mmol), with the gained reactant mixture in stirred overnight at room temperature.Remove acetone by Rotary Evaporators; Residue water and ethyl acetate dilution; Use ethyl acetate extraction, use the salt water washing, through MgSO
4Drying is filtered, evaporate to dryness, the crude product product, its through silica gel column chromatography (ethyl acetate/hexane=1:4) the 943mg product; Yield is 80%.
The EC of the hT1R1/hT1R3 umami receptor that the compound activating of embodiment 29 is expressed in HEK293 clone
50Be 0.1 μ M.
Embodiment 29
N-(2-benzyl chloride base)-N '-(2-(pyridine-2-yl) ethyl) oxamides
Adopt and embodiment 25 similar methods, utilize (2-chlorphenyl) methylamine, ethyl oxalate acyl chlorides and 2-(2-pyridine radicals) ethylamine to be prepared; Yield is 45%; M/e=318[M+1].
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.01 μ M.
Embodiment 30
N
1-(2-methoxyl group-4-methyl-benzyl)-N
2-(2-(5-picoline-2-yl) ethyl) oxamides
1H?NMR(CDCl
3，500MHz)：δ?2.29(3H，s)；2.33(3H，s)；2.97(2H，t，J＝6.5Hz)；3.71(2H，q，J＝6.5Hz)；3.83(3H5s)；4.40(2H，d，J＝6.2Hz)；6.68(1H，s)；6.69(1H，d，J＝7.7Hz)；7.02(1H，d，J＝7.9Hz)；7.09(1H，d，J＝7.5Hz)；7.40(1H，dd，J
1＝1.8Hz，J
2＝7.8Hz)；7.85(1H，br?t)；8.06(1H，br?t)；8.38(1H，s，J＝7.5Hz)。
13C?NMR(CDCl
3，500MHz)：18.3，21.8，36.5，39.1，39.6，55.5，111.5，121.3，122.3，123.0，129.9，131.3，137.4，139.6，150.0，155.7，157.7，159.7，160.1。
Elementary analysis: with regard to C
18H
21N
3O
3.1/4 H
2The calculated value of O: C, 65.97; H, 6.85; N, 12.15; Measured value: C, 66.10; H, 7.34; N, 12.17.MS(342，M+1)。White powder, fusing point=133.5-134 ℃.
The EC of the hT1R1/hT1R3 umami receptor that this compound activating is expressed in HEK293 clone
50Be 0.03 μ M.
This compound synthesizes by step listed in the following proposal, and the detailed description in each step of these 6 synthesis steps is also being provided subsequently.
Step 1: (25g adds K in acetone 0.164mol) (350mL) solution to 2-hydroxy-4-methyl benzoic acid
2CO
3(68g, 0.492mmol), (41mL 0.656mmol), added hot reflux 48 hours with the gained reactant mixture to add MeI then.After being cooled to room temperature, the gained reactant mixture is filtered, the filtrate evaporate to dryness gets crude product 2-methoxyl group-methyl 4 methylbenzoate.KOH (11.3g, 1.2 equivalents) is dissolved among the MeOH (300mL), above-mentioned crude product ester is added in the gained mixture, with this vlil 48 hours.After cooling, the gained reactant mixture with HCl (1N) acidified aqueous solution, is used ethyl acetate extraction.Organic layer salt water washing is through MgSO
4Drying is filtered and evaporate to dryness.Residue grinds to such an extent that 20g is the 2-methoxyl group-4-methyl benzoic acid (yield is 85%) of paste white solid with ethyl acetate/hexane.
Step 2: to 2-methoxyl group-4-methyl benzoic acid (20g, 120.4mmol), EDC (23.1g, 120.4mmol) and HOBt (16.3g 120.4mmol) dropwise adds NH in the mixture in carrene (1L)
3(7N MeOH solution, 52mL, 3 equivalents).Reactant mixture in stirred overnight at room temperature, is used HCl (1N), saturated NaHCO then in proper order
3The aqueous solution, water and salt water washing are through MgSO
4Drying is filtered and evaporate to dryness.Residue with ethyl acetate/hexane be recrystallized 16.5g 2-methoxyl group-4-methyl benzamide (yield is 83%).
Step 3: at 0 ℃ and N
2(14.55g dropwise adds borine-oxolane compound (1.0M in THF, 220mL, 2.5 equivalents) in anhydrous THF (50mL) solution 88.08mmol) to 2-methoxyl group-4-methyl benzamide under the atmosphere.Reactant mixture being heated to 60 ℃ then spends the night.With the reactant mixture cool to room temperature, (6N 37mL), heats reactant mixture 2 hours at 70 ℃ then carefully to add the HCl aqueous solution.After the cooling, add entry, gained solution is washed with ether.Water layer 0 ℃ of alkalization, is used K with the NaOH aqueous solution (10N)
2CO
3Saturated, use ethyl acetate extraction then.Organic layer salt water washing through the MgSO4 drying, is filtered evaporate to dryness and is got 8.5g (2-methoxyl group-4-aminomethyl phenyl) methylamine.(yield is 64%).
Step 4: under-78 ℃ and nitrogen protection, in anhydrous THF (500mL) solution of anhydrous acetonitrile (10.1mL, 191.83mmol, 3.3 equivalents), dropwise add n-BuLi (hexane solution of 2.5M, 69.8mL, 174.39mmol, 3 equivalents).The gained white suspension stirred 1 hour at-78 ℃, added anhydrous THF (30mL) solution of 2-bromo-5-picoline (10.0g, 58.13mmol, 1 equivalent) then.The gained reactant mixture kept 1 hour at-78 ℃, slowly was warmed to room temperature then, stirred 1 hour again.Add ice/water, separate each layer.Organic layer water and salt water washing are through MgSO
4Drying is filtered evaporate to dryness and is got 18g crude product 2-(5-picoline-2-yl) acetonitrile.In view of products obtained therefrom is very easy to volatilization, therefore under high vacuum, it is not carried out drying, so this product contains certain amount of solvent.
Step 5: under 0 ℃ and nitrogen protection, in anhydrous THF (100mL) solution of 18g crude product 2-(5-picoline-2-yl) acetonitrile, dropwise add borine-oxolane compound (1.0M THF solution, 232mL, 232.5mmol, 4 equivalents).Then the gained reactant mixture being heated to 60 ℃ spends the night.With the reactant mixture cool to room temperature, (6N 40mL), heats reactant mixture 2 hours at 70 ℃ then carefully to add the HCl aqueous solution.After the cooling, add entry, gained solution washs with ether.Water layer 0 ℃ of alkalization, is used K with the NaOH aqueous solution (10N)
2CO
3Saturated, use ether (5 x 100mL) extraction then.Organic layer is through MgSO
4Drying is filtered evaporate to dryness and is got 7.6g crude product 2-(5-picoline-2-yl) ethamine (the crude product yield is 96%).
When the evaporate to dryness ether, bath temperature remains on 25 ℃, because the boiling point of described amine is about 100 ℃.
Step 6: at N
2Protection is descended 2g (2-methoxyl group-4-aminomethyl phenyl) methylamine (from step 3) and Et
3N (triethylamine) (3.7mL, 2 equivalents) is at anhydrous CH
3Mixture among the CN (45mL) is cooled to 0 ℃, dropwise adds 2-chloro-2-oxo ethyl acetate (1.47mL, 1 equivalent).Add finish after, stirring at room 4 hours, (2.52g, 1.4 equivalents were from step 5) to add 2-(5-picoline-2-yl) ethamine then with reactant mixture.Reactant mixture was added hot reflux 24 hours.After the cooling, the solvent decompression is removed, residue is dissolved in the ethyl acetate, and order water and salt water washing are through MgSO
4Drying is filtered evaporate to dryness.Residue is through silica gel column chromatography (eluent: the hexane solution of 25-35% acetone), with the ethyl acetate/hexane recrystallization, with the ethanol/water recrystallization, get 650mg N then
1-(2-methoxyl group-4-methyl-benzyl)-N
2-(2-(5-picoline-2-yl) ethyl) oxamides (15%).
Embodiment 30-1
N
1-(2-methoxyl group-4-methyl-benzyl)-N
2The improvement of preparation of-(2-(5-picoline-2-yl) ethyl) oxamides and purifying
According to the synthesis strategy shown in the scheme 1, preparation N
1-(2-methoxyl group-4-methyl-benzyl)-N
2-(2-(5-picoline-2-yl) ethyl) oxamides.Following to synthetic description with reference in the compound number shown in this scheme.
Scheme 1
With 2-hydroxy-4-methyl-benzamide (15.1g, 0.1mol) and K
2CO
3(41.7g, 0.3mol) mixture in 1000mL acetone added hot reflux 1 hour, added Me then under this temperature
2SO
4(dimethyl suflfate).The gained mixture refluxes and spends the night.Then reactant mixture is filtered, filtrate concentrates.The gained residue was dissolved in 1000mL methyl alcohol/ammonia (1:1), stirring at room 3 hours.After solvent removed, residue with EtOAc/PE be recrystallized 102g 2-methoxyl group-4-methyl-benzamide (yield is 61%).
1H?NMR(400MHz，DMSO?d6)：δ?7.72(d，J＝7.6Hz，1H)，7.57(br?s，1H)，7.46(br?s，1H)，6.92(s，1H)，6.81(d，J＝7.6Hz，1H)，3.85(s，3H)，2.31(s，3H)。
The preparation of step 2:2-methoxyl group-4-methyl-benzylamine hydrochloride:
At 0 ℃ and N
2Protection down, to 2-methoxyl group-4-methyl-benzamide (41g, add in 1500mL THF solution 0.25mol) lithium aluminium hydride reduction (19g, 0.5mol).The gained mixture is added hot reflux to spend the night.After the cooling, with reactant mixture with 10% NaOH aqueous solution cancellation.Reactant mixture is filtered, filtrate concentrate the crude product product.Residue is dissolved in Et
2Among the O (ether), add HCl/Et then
2O solution.Collect the gained sediment, with TMBE wash the structure fragment A (35g, yield are 75%) in the scheme 1.
1H?NMR(300MHz，DMSO-d
6)：δ?8.15(br?s，3H)，7.25(d，J＝7.5Hz，1H)，6.88(s，1H)，6.77(d，J＝7.5Hz，1H)，3.94-3.86(m，2H)，3.79(s，3H)，2.30(s，3H)。
The preparation of step 3:2-(5-picoline-2-yl) acetonitrile:
Under-78 ℃ and nitrogen protection, in anhydrous THF (500mL) solution of anhydrous acetonitrile (10.1mL, 191.83rnmol, 3.3 equivalents), dropwise add n-BuLi (hexane solution of 2.5M, 69.8mL, 174.39mmol, 3 equivalents).The gained white suspension stirred 1 hour at-78 ℃, added anhydrous THF (30mL) solution of 2-bromo-5-picoline (10.0g, 58.13mmol, 1 equivalent) then.Reactant mixture was kept 1 hour at-78 ℃, slowly be warmed to room temperature then, stirred again 1 hour.Add ice/water, separate each layer.Organic layer water and salt water washing are through MgSO
4, filtering, evaporate to dryness gets the 18g crude product, and this crude product is used for the next step reaction without being further purified.
The preparation of step 4:2-(5-picoline-2-yl) ethylamine hydrochloride:
Under 0 ℃ and nitrogen protection, in anhydrous THF (100mL) solution of 18g crude product 2-(5-picoline-2-yl) acetonitrile, dropwise add borine-dimethyl sulfide compound (the THF solution of 10M, 23.2mL, 232.5mmol, 4 equivalents).Then the gained reactant mixture being heated to 60 ℃ spends the night.With the reactant mixture cool to room temperature, (6N 40mL), heats reactant mixture 2 hours at 70 ℃ then carefully to add the HCl aqueous solution.After the cooling, add entry, gained solution washs with ether.With the NaOH aqueous solution (10N) alkalization, use K at 0 ℃ of water layer
2CO
3Saturated, use ether (5 x 100mL) extraction then.Organic layer is through MgSO
4Drying is filtered, and evaporate to dryness gets the 7.6g crude product.With dissolving crude product at CH
2Cl
2In, use HCl/Et then
2O handle 2-(5-picoline-2-yl) ethylamine hydrochloride (4g is 40% with compound 3 rates of collecting), this compound is used for next step reaction without being further purified.
Step 5:N
1-(2-methoxyl group-4-methyl-benzyl)-N
2The preparation (one kettle way) of-(2-(5-picoline-2-yl) ethyl) oxamides:
Under 0 ℃ and nitrogen protection, in anhydrous acetonitrile (45mL) mixture of 1.8g (2-methoxyl group-4-aminomethyl phenyl) methylamine hydrochloride and triethylamine (5.1mL, 3 equivalents), dropwise add 2-chloro-2-oxo ethyl acetate (1.47mL, 1 equivalent).After adding, reactant mixture stirring at room 2 hours, is added 2-(5-picoline-2-yl) ethamine (2.52g, 1.4 equivalents).Reactant mixture was added hot reflux 24 hours.Except that after desolvating, residue is dissolved in the ethyl acetate, order water and salt water washing are through MgSO
4Drying is filtered evaporate to dryness.Residue is used ethyl alcohol recrystallization with methyl tertiary butyl ether(MTBE) (20mL) washing, obtains the N of 1.3g white powder
1-(2-methoxyl group-4-methyl-benzyl)-N
2-(2-(5-picoline-2-yl) ethyl) oxamides (yield is 30%).M/e=342[M+1]; M.p.=133.5-134 ℃;
1H NMR (400MHz, CDCl
3): δ 8.38 (s, 1H), 8.07 (br s, 1H), 7.85 (br s, 1H), 7.40 (dd, J
1,=1.6Hz, J
2=8Hz, 1H), 7.12 (d, J=7.6Hz, 1H), 7.03 (d, J=7.6Hz, 1H), 6.71 (d, J=7.2Hz, 1H), 6.68 (s, 1H), 4.42 (d, J=6.4Hz, 2H), 3.84 (s, 3H), 3.71 (q, J=6.4Hz, 2H), 2.97 (t, J=6.4Hz, 2H), 2.33 (s, 3H), 2.30 (s, 3H);
13C NMR (400MHz, CDCl
3): 18.6,22.2,36.9,39.4,39.9,55.8,111.9,121.6,122.6,123.3,130.2,131.6,137.7,139.9,150.5,156.1,158.1,160.0,160.5; Elementary analysis: with regard to C
18H
21N
3O
3.1/4H
2The calculated value of O: C, 65.97; H, 6.85; N, 12.15, measured value: C, 66.10; H, 7.34; N, 12.17.
Embodiment 30-2
N
1-(2-methoxyl group-4-methyl-benzyl)-N
2The optional improvement of preparation of-(2-(5-picoline-2-yl) ethyl) oxamides and purifying:
N
1-(2-methoxyl group-4-methyl-benzyl)-N
2-(2-(5-picoline-2-yl) ethyl) oxamides also can be prepared according to scheme 2 described synthesis strategies.Following to synthetic description with reference in the compound number shown in this scheme.
Scheme 2
Preparation 2-methoxyl group as described below-4-methyl-benzylamine and 2-methoxyl group-4-methyl-benzylamine hydrochloride
The preparation of step 3:2-(5-picoline-2-yl) acetonitrile:
Under-78 ℃ and nitrogen protection, in dry THF (500mL) solution of anhydrous acetonitrile (10.1mL, 191.83mmol, 3.3 equivalents), dropwise add n-BuLi (hexane solution of 2.5M, 69.8mL, 174.39mmol, 3 equivalents).The gained white suspension was stirred 1 hour at-78 ℃, add dry THF (30mL) solution of 2-bromo-5-picoline (10.0g, 58.13mmol, 1 equivalent) then.Reactant mixture was kept 1 hour at-78 ℃, slowly be warmed to room temperature then, stirred again 1 hour.Add frozen water, separate each layer.Organic layer water and salt water washing are through MgSO
4Drying is filtered, and evaporation gets the 18g crude product.(eluent PE/EtOAc=15:1) gets 2-(5-picoline-2-yl) acetonitrile (6.2g, productive rate are 80%) through purification by silica gel column chromatography with crude product.
1H?NMR(300MHz，CDCl
3)：δ?8.40(d，J＝3.0Hz，1H)，7.54(dd，J
1＝3.0Hz，J
2＝6.0Hz，1H)，7.32(d，J＝6.0Hz，1H)，3.90(s，2H)，2.40(s，3H)。
The preparation of step 4:2-(5-picoline-2-yl) ethamine:
To crude product 2-(5-picoline-2-yl) acetonitrile (3g, saturated NH 22.7mmol)
3Add the 0.5g Raney Ni in-MeOH (50mL) solution.Then reactant mixture hydrogenation under room temperature and 6MPa condition is spent the night.Filter reaction mixture, filtrate vacuum concentrate 2-(5-picoline-2-yl) ethamine (3.02g, yield are 97%), this product is without being further purified direct use.Warp
1H-NMR detects and does not find impurity.
1H?NMR(400MHz，DMSO-d
6)：δ?8.27(br?s，1H)，7.46(d，J＝8.4Hz，1H)，7.10(d，J＝8.4Hz，1H)，2.69-2.83(m，4H)，2.21(s，3H)。
The preparation of step 5:2-(2-methoxyl group-4-methyl-benzyl amino)-2-oxo ethyl acetate:
Under 0 ℃ and nitrogen protection to 2-methoxyl group-4-methylbenzylamine hydrochloride (10g, 0.053mol) and dropwise add in dry acetonitrile (100mL) solution of triethylamine (30g) 2-chloro-2-oxo ethyl acetate (7.28g, 0.053mol).Add finish after, with reactant mixture stirring at room 4 hours.Solvent removed in vacuo, residue are dissolved in the ethyl acetate, with salt water washing (100mL X 3), through Na
2SO
4Drying, except that getting title compound 5 (12g, yield are 89%) after desolvating, this compound is used for the next step reaction without being further purified.Warp
1H-NMR detects and does not find impurity.
1H?NMR(400MHz，DMSO-d
6)：δ?9.10(br?s，1H)，6.98(d，J＝8Hz，1H)，6.79(s，1H)，6.70(d，J＝8Hz，1H)，4.19-4.27(m，4H)，3.77(s，3H)，2.26(s，3H)，1.26(t，J＝7.2Hz，3H)。
Step 6:N
1-(2-methoxyl group-4-methyl-benzyl)-N
2The preparation of-(2-(5-picoline-2-yl) ethyl) oxamides:
(36.9g, 0.147mol) (30g adds triethylamine (120mL) and dry acetonitrile (800mL) in mixture 0.22mol) with structure fragment B to compound 5.Reactant mixture was added hot reflux 34 hours.Vacuum evaporation removes and desolvates, and residue is dissolved in the ethyl acetate (1L), washes (300mL X 3) with water, through Na
2SO
4Dry.Filter, solvent removed in vacuo, residue obtains 17g N with ethanol/water (10:1) recrystallization
1-(2-methoxyl group-4-methyl-benzyl)-N
2-(2-(5-picoline-2-yl) ethyl) oxamides (yield is 44%).
1H?NMR(300MHz，DMSO-d
6)：δ?8.83(m，2H)，8.30(d，J＝2.1Hz，1H)，7.49(dd，J
1＝2.1Hz，J
2＝8.4Hz，1H)，7.20(d，J＝7.8Hz，1H)，6.91(d，J＝7.5Hz，1H)，6.79(s，1H)，6.68(d，J＝7.5Hz，1H)，4.23(d，J＝6Hz，2H)，3.77(s，3H)，3.43-3.50(q，J
1＝7.5Hz，J
2＝14.4Hz，2H)，2.89(t，J＝7.5Hz，2H)，2.23(s，3H)，2.26(s，3H)。
Compare with the yield (40%) of previous embodiment, the method for present embodiment is by with column chromatography purification compound 4 with use H
2/ Raney Ni replaces BH
3-SMe
2Make yield rise to 85%.And, in this embodiment one kettle way among the previous embodiment is prepared N
1-(2-methoxyl group-4-methyl-benzyl)-N
2-(2-(5-picoline-2-yl) ethyl) oxamides is divided into two steps.Among this embodiment, make productive rate bring up to 44% from 30% of previous embodiment one kettle way by purifying 2-(2-methoxyl group-4-methyl-benzyl amino)-2-oxo acetic acid esters, the one kettle way of wherein previous embodiment is purifying 2-(2-methoxyl group-4-methyl-benzyl amino)-2-oxo acetic acid esters not.
The delicate flavour experiment that utilizes people group member to carry out:
Group member's routine is selected: flavor tests person's basic screening: the ability that test may be carried out classification and identification (rank and rate) to the intensity of the solution of representing 5 kinds of primary tastes as group member's experimenter.The group member carries out classification and identification to each the intensity of 5 variable concentrations of following 5 kinds of compounds: sucrose (sweet taste), sodium chloride (saline taste), citric acid (tart flavour), caffeine (bitter taste) and sodium glutamate (delicate flavour).In order to take one's test, the group member need carry out correct classification and identification to sample with regard to intensity, and wrong number of times occurring should be reasonable.
Elementary flavor tests: selected according to the method described above group member, these personnel are considered to carry out elementary flavor tests.This elementary flavor tests is used to assess the intensity of the primary taste (basictastes) and the peculiar smell (off-tastes) of noval chemical compound.Several group members (n=5) are 1 group, (usually concentration range is 1-100 μ M to taste the compound of about 5 concentration, form with semilog circulation (half-log cycle), as 1,3,10,30 and 100 μ M), these compounds are dissolved in the water and are dissolved in the 12mMMSG solution to estimate the enhancing degree.The group member goes up in the intensity dimension (labeled magnitudescale) that indicates and assert described 5 kinds of primary tastes (sweet taste, saline taste, tart flavour, bitter taste and delicate flavour) and peculiar smell (as chemical taste, metallic taste and sulphur taste).The sample that is in every part of 10mL of room temperature is provided.The purpose of test is to determine not have the maximum concentration of perceptible peculiar smell, and has determined whether tangible delicate flavour or delicate flavour is had humidification when arbitrary test concentrations.
If compound is effectively and does not have perceptible peculiar smell, then through professional (member of professional group) it tested in more massive research.
The member's of professional group selection: the experienced group member of specialty further estimates the compound by elementary flavor tests.
The member of professional group selects from the flavor tests personnel that qualify in a large number.These group members will be through further at the training of delicate flavour, and this training is to utilize the combination of MSG and IMP to carry out classification and identification test.The group member utilizes delicate flavour solution to finish a series of classifications, identification and the test of distinguishing mutually with reference substance.In classification with assert in the test, the group member has estimated the concentration (3,6,12,18mM MSG) of the difficult evaluation of the concentration (0,6,18,36mM) of the easy evaluation of the MSG aqueous solution and the MSG aqueous solution.
Professional group is to the test of compound: estimate different through the compound of the compound of professional group's test and control experiment.Provide control sample (12mM MSG+100 μ M IMP) to the group member, require its in-5 to+5 mark scopes according to sample being assert that (mark :-5=lacks a lot than the delicate flavour of reference substance with reference substance different on delicate flavour; 0=has identical delicate flavour with reference substance; + 5=is howed a lot than the delicate flavour of reference substance).Specimen is the solution with different amount MSG, IMP and compound.Typically, each is taken turns test and control sample and a plurality of specimen will be compared.Test generally includes the different samples with various MSG and IMP concentration, and blind (blind) sample that comprises reference substance itself, is the degree of accuracy of estimating for the assessment panel member like this.The result of flavor tests is disclosed in the table 3, and the result shows with 100 μ M IMP+MSG and compare that The compounds of this invention has delicate flavour or can strengthen delicate flavour when 3 μ M+MSG.Having and not having in the sample of 12mM MSG,, compound is tested with respect to reference substance.All samples all are 10ml volumes under the room temperature condition.Carry out the two-wheeled test to estimate the repeatability of group at each test compounds.
Can adopt to above-mentioned similar mode the flavor tests of product prototype (Product Prototype) and to carry out.
Table 3: delicate flavour test result
| Compound number | Chemical name | The taste data |
| Embodiment 1 | N-(heptan-the 4-yl) benzo [d] [1,3] dioxole-5-formamide | 12mM MSG+3 μ M compound is identical with 12mM MSG+100 μ M IMP intensity |
| Embodiment 5 | (R)-2-(benzo [d] [1,3] dioxole-6-formamido group)-4-methylvaleric acid methyl esters | 12mM MSG+10 μ M compound is identical with 12mM MSG+100 μ M IMP intensity |
| Embodiment 18 | (R)-and N-(1-methoxyl group-4-methylpent-2-yl)-3, the 4-dimethyl benzamide | 12mM MSG+3 μ M compound is identical with 12mM MSG+100 μ M IMP intensity |
| Embodiment 19 | (R)-2-(2,3-dimethyl furan-5-formamido group)-4-methylvaleric acid methyl esters | 12mM MSG+10 μ M compound is identical with 12mM MSG+100 μ M IMP intensity |
| Embodiment 20 | 4-methoxyl group-N-(1-methoxy-3-methyl-butyl)-3-methyl-benzamide | 12mM MSG+3 μ M compound is identical with 12mM MSG+100 μ M IMP intensity |
| Embodiment 24 | N-(2,4-dimethoxy-benzyl)-N '-(2-pyridine-2-base-ethyl)-oxamides | 12mM MSG+1 μ M compound is identical with 12mM MSG+100 μ M MP intensity |
| Embodiment 26 | N-(2-methoxyl group-4-methyl-benzyl)-N '-(2-(5-picoline-2-yl) ethyl) oxamides | 12mM MSG+1 μ M compound is identical with 12mM MSG+100 μ M IMP intensity |
| Embodiment 30 | N 1-(2-methoxyl group-4-methyl-benzyl)-N 2-(2-(5-picoline-2-yl) ethyl) oxamides | 12mM MSG+0.3 μ M compound is identical with 12mM MSG+100 μ MIMP intensity |
| Embodiment 22 | (s)-N-(2,3-dihydro-1H-indenes-1-yl)-4-methoxyl group-3-methyl benzamide | 12mM MSG+1 μ M compound is identical with 12mM MSG intensity with the identical 1 μ M compound of 12mM MSG+100 μ M IMP intensity |
Embodiment 31
Utilize ethanol stoste (Ethanol Stock Solution) preparation soup
The compound of table 3 is diluted to 1000 times of ideal concentration in soup with the ethanol (200 proof ethanol) of 200 alcoholic strengths.Can and heat the ultrasonic processing of described compound to guarantee its dissolving fully in ethanol.Soup by clear soup base-material (bouillon base) preparation prepares by the following method: 6g julienne base-material is added in the 500mL hot water that is contained in glass bowl or the china bowl.Water is heated to 80 ℃.The concentration of MSG in the clear soup of dissolving is 2.2g/L, does not add IMP.After treating the dissolving of clear soup base-material, in the soup product, add above-mentioned ethanol stoste.The 1000x ethanol stoste of 0.5mL is gone into by 500mL Tonga, and final concentration of alcohol is 0.1%.If ethanol interfere with the taste of soup, then can prepare the ethanol stoste of higher concentration, prerequisite is as long as this compound is soluble in this case.
Embodiment 32
The preparation of potato chips
By The compounds of this invention is mixed the salt mixture for preparing The compounds of this invention with salt, the standard of mixing is just can satisfy requirement to compound concentration when by weight 1.4% salt mixture being added back in the potato chips.If wish finally to contain on the potato chips compound of 1ppm, then need the compound of 7mg is mixed with 10g salt.With mortar and pestle compound is ground with salt, compound is fully mixed with salt.Utilize agitator (blender) potato chips to be fragmented into the fritter of homogeneous.Every 98.6g potato chips take by weighing the 1.4g salt mixture.The potato chips piece is heated 50 seconds earlier up to heating in microwave.Fritter is layered on the aluminium-foil paper of bulk.Salt mixture evenly is sprinkling upon on the potato chips.Then potato chips are placed in the polybag to guarantee that all salt are contained in the sack too.Rock salt mixture and potato chips then, to guarantee that salt can be evenly distributed on the potato chips.
Embodiment 33
The cocktail mixture (bloody mary mix) of fragrant peppery tomato juice or the preparation of tomato juice vodka
The form of The compounds of this invention with dry ingredient is added in the fragrant peppery blend (spice blend), and fully blend, the peppery blend of described perfume (or spice) can be chosen wantonly and contain sodium glutamate.The peppery blend of perfume (or spice) is distributed in a part of tomato puree, and blend further is blended into this blend pastel in the remaining tomato puree.This pastel of dilute with water prepares the cocktail mixture of fragrant peppery tomato juice (spicy tomato juice) or the preparation of tomato juice vodka then.
Embodiment 34
People's taste test of low sodium tomato juice
In order to estimate the ability that The compounds of this invention strengthens the delicate flavour of low sodium tomato juice (its natural contain a certain amount of sodium glutamate), carry out the test of people's taste.
Sample preparation methods
Preparation is used for the final tomato juice sample of flavor tests, it contains the previously prepared low sodium tomato juice stoste of 90% (by volume), and (pH 4.2,80～100mg Na/8oz, naturally occurring MSG are 16mM), 5% (by volume) stoste and 5% (by volume) the The compounds of this invention stoste that to be formulated into the final sodium level that makes final juice be selected level.Selected oxamides compound of the present invention is dissolved among the LSB (low na phosphates buffer solution), obtains stoste, the concentration of this stoste is 20 times of required ultimate density in the tomato juice finished product.Required final na concn is 73.6mM (being 400mg sodium in 8oz juice) in most experiments in the tomato juice finished product, therefore prepares the NaCl stoste that NaCl concentration is 1.48M.With the 1M citric acid soln pH of stoste is adjusted to 4.2, then stoste is carried out ultrasonic to guarantee that the compound that adds can dissolve fully.In order to prepare 1,000mL finally is used for the tomato juice sample of flavor tests, adds 50mL test compounds stoste and the above-mentioned sodium chloride stoste of 50mL in the previously prepared low sodium tomato juice stoste of 900mL.
The test of people's taste
16 people carry out this flavor tests.Before test, at least 1 hour, limit tester's food and drink (except the water).Gargle with oral cavity cleaning at edible crispbread (cracker) of test Pretesting person and water.In room temperature the 15mL sample is contained in the 2oz. specimen cup for test usefulness.Group member's water between two samples of test is gargled, and the edible crispbread of suggestion is flavoursome to remove, and tests next sample then.At each test phase, provide (having different blind numberings) in stochastic equilibrium order (random counterbalancedorder) mode with sample.Require the group member to estimate delicate flavour (umaminess) (delicate flavour level), go up in non-structure linear-scale (unstructured line scale) (mark is 0-10) and sample is estimated repeated experiments.Rest in 5 minutes is arranged between two test phases, advance to carry out altogether 4 experiments in 2 day time.The sample of tasting is as described below:
| Specimen |
| 400mg Na/8oz tomato juice |
| 400mg Na+3 μ M compound 24/8oz tomato juice |
| 400mg Na+3 μ M compound 30/8oz tomato juice |
Each group member and every score of taking turns experiment are averaged, utilize two-way ANOVA (factor: group member and sample) and the multiple comparative experiments of Deng Kenshi (Duncan ' s multiple comparisontest) (α=0.05) that score is estimated to judge the significant difference on the strength grading.The result is summarized as follows:
Table G. tomato juice flavor tests result
| Compound | Chemical name | The taste data |
| 24 | N 1-(2, the 4-dimethoxy-benzyl)-N 2-(2-(pyridine-2-yl) ethyl) oxamides | 3 μ M compounds make the delicate flavour of 16mM sodium glutamate (natural existence) in low sodium tomato juice strengthen 1.4-1.5 doubly |
| 30 | N 1-(2-methoxyl group-4-methyl-benzyl)-N 2-(2-(5-picoline-2-yl) ethyl) oxamides | 3 μ M compounds make the delicate flavour of 16mM sodium glutamate (natural existence) in low sodium tomato juice strengthen 1.8-1.9 doubly |
Embodiment 35
Prepare the delicate flavour concentrate composition by spray-drying
As described in other place of the present invention, the umami compound that the present invention discloses is effective especially; In order to prepare condiment mixture and/or final edible composition, the condiment concentrate composition of wishing the preparation dilution suitably.Following spray-drying step is used to prepare two kinds of such solid seasoning concentrate compositions, a kind of amide compound that comprises 0.10% (w/w) embodiment 1, and another kind contains the oxamides compound of embodiment 24.
The NeobeeM-5 medium chain triglyceride composition that 344.74 grams can be buied places 2 liters of stainless steel cylindrical chambers, is heated to 200 ℉ on the steam platform, stirs with the Lightnin blender.The amide compounds (compound 1) of 18.14 gram embodiment 1 are slowly added under the vigorous stirring situation, mixes 30 minutes up to described compound fully dissolve and solution becomes get limpid, thereby the pre-blend composition of formation delicate flavour reduces the temperature to 180 ℉ then.
In another 2 liters of stainless steel cylindrical chambers, stir 2721.60g water with the Lightnin blender, be heated to 140 ℉, the speed with the Lightnin blender is set in 500rpm then, produces whirlpool, slowly add 1451.52g N-Lok 1930 modified food starch, mixed 20 minutes.Then the pre-blend composition of the above-mentioned delicate flavour of 1814.40g slowly is added in the described N-lok aqueous solution, mixed 30 minutes with 500rpm, temperature drops to 120 ℉, then with mixture Gaulin refiner (E type) homogenizing, phase I is arranged on 2000psi (pound/square inch), second stage is arranged on 500psi, forms emulsion.
Utilize Stock-Bowen Conical Laboratory Spray-Aire spray dryer with the gained emulsion spray drying, inlet temperature is 203 ℃, outlet temperature is 119 ℃, flow velocity is 160ml/ minute, air pressure is 40psi, forms the powder that 1306.20 grams contain 1% embodiment, 1 compound.This is equivalent to productive rate is 71.99%, perhaps has been equivalent to lose in vacuum chamber 18.01% product.1 pound of (453.6g) spray-dired powder is mixed in 40 quarts of Hobart planetary-type mixers (Hobart planetary mixer) with the 10DE maltodextrin (Tate andLyIe) of 9.0 pounds (4082.4g), mixed 20 minutes, obtain dry delicate flavour condiment concentrate powder, it contains embodiment 1 compound of 0.10% (wt/wt).HPLC the analysis showed that and accounts for 82% of compound 1 theoretical amount.Utilize identical processing method preparation to contain the delicate flavour condiment concentrate composition of 0.1% (wt/wt) embodiment, 24 compounds (compound 24).Especially, the oxamides compound of 349.272g Neobee M-5 and 13.608g embodiment 24 mixed up to dissolving forming the pre-blend composition of delicate flavour at 200 ℉, solution temperature is reduced to 180 ℉.
1451.52g N-Lok1930 and 2721.60g water mixed and heating up to reaching 140 ℉, utilize the Lightnin blender to produce whirlpool at 500rpm, add the pre-blend composition of 1814.40g delicate flavour, mixed 30 seconds at 500rpm, then solution is maintained 120 ℉, with Gaulin refiner (E type) homogenizing.Gained emulsion is spray-dried, and inlet temperature is 203 ℃, and outlet temperature is 119 ℃, and flow velocity is 160ml/ minute, and air pressure is 40psi, obtains the spray-dired powder of 1400.72 grams, and it contains embodiment 24 compounds of 0.75% (wt/wt).
The powder that 1.334 pounds (605.1024g) is spray-dried mixes with 8.666 pounds of (3930.8976g) 10DE maltodextrins (Tate and LyIe), obtain final dry delicate flavour condiment concentrate powder, this powder contains embodiment 24 compounds of 0.10% (wt/wt).
Embodiment 36
Replace the MSG in the sausage flavoring
General introduction:
The delicate flavour condiment concentrate composition that comprises embodiment 1 or 24 compounds is used to prepare sausage seasoning mixture and the sausage example of using for salami itself, and compares with the contrast sausage that contains and do not contain MSG in the test of people's taste.People tester compares and reports that the sausage comparison that contains embodiment 1 compound and embodiment 24 compounds has higher delicate flavour, appreciable denseer saline taste and denseer fragrant pungent according to sausage to sample.
The preparation of sausage:
By the following table ingredients listed is carried out dry blend, the salami seasoning mixture of three kinds of different dryings of preparation carries out aquation then again in the process of the corresponding sausage of preparation.A control sample of seasoning mixture (table 36-1a, b) does not contain MSG, does not contain The compounds of this invention yet.The MSG (table 36-2a, b) that second sample of seasoning mixture and corresponding sausage contain interpolation.The delicate flavour concentrate composition that the 3rd sample of seasoning mixture and corresponding sausage contain interpolation (according to embodiment 34 preparations), it contains the compound 1 and 24 (table 36-1a, b) of 0.1% (wt/wt).
Table 36-1a: the salami seasoning mixture that does not contain MSG
| Composition | Gram | Prescription % (wt/wt) |
| Salt (Morton Salt) | 64.16 | 32.08 |
| Sugar (C﹠H # 801461) | 37.74 | 18.87 |
| Chilli powder (Pacific Spice SA#1406) | 37.74 | 18.87 |
| Garlic powder (American Ingredients #5557) | 30.56 | 15.28 |
| Fennel seed through baking and banking up with earth (Spice Island 6C08B) | 11.32 | 5.66 |
| Black pepper 28 orders (Pacific Spice SA#01406) | 9.44 | 4.72 |
| Parsley sheet (Pacific Spice SA#C1406) | 3.78 | 1.89 |
| The anise seed (retail Kroger 09BK) that grinds | 3.38 | 1.69 |
| Capsicum (Pacific Spice SA#C1406) | 1.88 | 0.94 |
| Amount to | 200 | 100 |
| Analysis to 10% solution of drying composite | ||
| pH | 5.00 | |
| Salt % | 31.53 | |
| Brix Scale (Brix) | 6.60 |
Table 36-1b: sausage goods (not having MSG)
| Composition | Gram | Prescription % (wt/wt) |
| The pork (20% fat) that grinds | 280.68 | 93.56 |
| The salami seasoning mixture that does not contain the drying of MSG | 15.9 | 5.30 |
| Water | 3.42 | 1.14 |
| Amount to | 300 | 100 |
Table 36-2a: the salami seasoning mixture that contains MSG
| Composition | Gram | Prescription % (wt/wt) |
| Salt (Morton Salt) | 62.96 | 31.48 |
| Sodium glutamate (Ajinomoto#310704) | 3.70 | 1.85 |
| Sugar (C﹠H#801461) | 37.04 | 18.52 |
| Chilli powder (Pacific Spice SA#1406) | 37.04 | 18.52 |
| Garlic powder (American Ingredients #5557) | 30.00 | 15.00 |
| Fennel seed through baking and banking up with earth (Spice Island 6C08B) | 11.12 | 5.56 |
| Black pepper 28 orders (Pacific Spice SA#01406) | 9.26 | 4.63 |
| Parsley sheet (Pacific Spice SA#C1406) | 3.70 | 1.85 |
| The anise seed (retail Kroger 09BK) that grinds | 3.32 | 1.66 |
| Capsicum (Pacific Spice SA#C1406) | 1.86 | 0.93 |
| Amount to | 200 | 100 |
| Analysis to 10% solution of drying composite | ||
| pH | 5.00 | |
| % salt | 31.53 | |
| Brix Scale | 6.60 |
Table 36-2b: sausage goods (containing MSG)
| Composition | Gram | Prescription % (wt/wt) |
| The pork (20% fat) that grinds | 280.41 | 93.47 |
| The salami seasoning mixture that contains the drying of MSG | 16.17 | 5.39 |
| Water | 3.42 | 1.14 |
| Amount to | 300 | 100 |
Table 36-3a: the salami seasoning mixture that contains 0.5ppm compound 1 and 0.7ppm compound 24
| Composition | Gram | Prescription % (wt/wt) |
| Salt (Morton Salt) | 61.60 | 31.37 |
| The condiment concentrate that contains 0.10% compound 1 | 1.82 | 0.92 |
| The condiment concentrate that contains 0.10% compound 24 | 2.54 | 1.29 |
| Sugar (C﹠H # 801461) | 36.24 | 18.45 |
| Chilli powder (Pacific Spice SA#1406) | 36.24 | 18.45 |
| Garlic powder (American Ingredients #5557) | 29.34 | 14.95 |
| Fennel seed through baking and banking up with earth (Spice Island 6C08B) | 10.88 | 5.54 |
| Black pepper 28 orders (Pacific Spice SA#01406) | 9.06 | 44.61 |
| Parsley sheet (Pacific Spice SA#C1406) | 3.62 | 1.85 |
| The anise seed (retail Kroger 09BK) that grinds | 3.26 | 1.67 |
| Capsicum (Pacific Spice SA#C1406) | 1.82 | 0.92 |
| Amount to | 200 | 100 |
| Analysis to 10% solution of drying composite | ||
| pH | 5.00 | |
| % salt | 31.53 | |
| Brix Scale | 6.60 |
Table 36-3b: sausage goods
| Composition | Gram | Prescription % (wt/wt) |
| The pork (20% fat) that grinds | 280.35 | 93.45 |
| The salami seasoning mixture that contains the drying of compound 1 (9ppm) and compound 24 (13ppm) | 16.23 | 5.41 |
| Water | 3.42 | 1.14 |
| Amount to | 300 | 100 |
Sensory evaluation:
10 professional flavor tests persons are through training to differentiate the intensity of following taste attribute: saline taste, delicate flavour/meat flavour, delicate flavour (umami), broth-like flavor (brothiness), bitter taste, aftertaste (linger) and peculiar smell (offflavors).Classification-identification strength test is used to estimate the salami sample.Classification assert that (rank rating) is a kind of distinctiveness test, whether is used to judge the sense organ gap between can the different samples of perception.The sample that is used to estimate is the salami, the salami that contains MSG that do not contain MSG, contain compound 1 and 24 but do not contain the salami of MSG.The group member estimated 3 of 1 ounce of salami through at random, the sample of blind coding, sample temperature is 140 ℉, and delicate flavour, saline taste, fragrant pungent carried out classification in the 0-10 yardstick: 0 for intensity is minimum, and 10 is that intensity is the highest, and the mark of each class is averaged.
Table 36c: the average mark of each class taste of salami
| Delicate flavour | Fragrant pungent | Saline taste | |
| Contain MSG | 6.13 | 5.42 | 5.24 |
| Do not contain MSG | 4.70 | 5.88 | 5.56 |
| Contain compound 1 and 24 | 6.34 | 6.42 | 5.97 |
Conclusion: the group member can point out the difference between the sample:
A. delicate flavour: it is that delicate flavour is minimum that the group member will not have the sample classification of MSG, and the sample classification that will contain flavour enhancer compound 1 and 24 is that delicate flavour is the highest.
B. saline taste: the sample classification that the group member will be contained MSG is that saline taste is minimum, and the sample classification that will contain flavour enhancer compound 1 and 24 is that saline taste is the highest.
C. fragrant pungent: the sample classification that the group member will be contained MSG is that fragrant pungent is minimum, and the sample classification that will contain flavour enhancer compound 1 and 24 is that fragrant pungent is the highest.
Embodiment 37
Part is replaced the MSG that makes things convenient in the noodle soup
General introduction:
The mixture of embodiment 1 and 24 compounds is used for preparing again and makes things convenient for noodle soup so that its MSG that contains only is 1/3 of contrast amount, by people's taste test with its with contain the contrast soup of full dose MSG and only contain the MSG normal amount 1/3 another contrast soup and compare.People tester can distinguish the contrast soup that contains full dose MSG and only contain the difference of delicate flavour between 1/3 the contrast soup of MSG normal amount, but can not distinguish the contrast soup and the difference of soup on delicate flavour of the two kinds of compounds of 1/3 and the present invention that contain normal amount MSG of preparation again that contains full dose MSG.
The preparation process of noodle soup sample:
Make things convenient for the preparation of noodle soup: following step is used to prepare 3 kinds of different instant noodles soup condiment blends, and it can be added to well-done the convenience in the noodle soup, is used for the test of people's taste.A kind of contrast flavoring blend contains full load amount MSG (table 1a, 1b and 1c).The second contrast flavoring blend contains 1/3 (table 2a, 2b and 2c) of MSG load.The 3rd flavoring blend comprises 1/3 of the condiment concentrate composition that contains compound 1 and 24 and MSG load.
Instant noodles soup condiment mixture:
Will be in table 37-1a, 37-2a, 37-3a listed dry ingredient blend utilizes the kitchen auxiliary mixer to stir 10 minutes with splash bar in 6 quarts of bowls, carries out manual blend with the rubber shovel then, reaches range estimation evenly.Seasoning mixture with drying before preparation soup leaves in the airtight food bag of polyurethane.Make things convenient for noodle soup with this flavoring with hot water preparation according to the ratio among table 37-1c, 37-2c, the 37-3c then.The components in proportions that is used for noodle soup easy to prepare (in fact also containing noodles) is listed in table 37-1c, 37-2c, 37-3c, but these samples are not tasted through reality.
Table 37-1a: instant noodles soup condiment mixture (full dose MSG)-control formula A
| Composition | Prescription % (wt/wt) |
| Salt (Morton Salt) | 31.53 |
| Sodium glutamate (Ajinomoto) | 15.24 |
| From dissolubility yeast extract (Sensient#945) | 0.79 |
| Hydrolyzed vegetable protein (Basic Food Flavors#C-303) | 5.25 |
| Ajitide?I+G(Ajinomoto) | 0.26 |
| Beans sauce powder (Nikken#5310) | 11.04 |
| Garlic powder (American Food Flavors, Inc #GA45) | 9.25 |
| Chicken powder (Henningson C-100-1B-AR #730) | 9.04 |
| Chicken flavouring (chicken flavor) (Mastertaste #F42X32) | 5.78 |
| Onion powder (Elite Spice #516) | 4.20 |
| Sugar, graininess (C﹠H) | 2.57 |
| Chicken cosmetics (powdered chicken Fat) (Henningson#732) | 2.52 |
| Turmeric (McCormick) | 1.05 |
| White pepper (Pacific Natural Spices) | 0.63 |
| The celery powder (Food Source, Inc#60) | 0.53 |
| Citric acid (ADM) | 0.32 |
| Amount to | 100.00％ |
Table 37-1b: make things convenient for the preparation (being prepared) of noodle soup with noodles
| Composition | Gram | Prescription % (wt/wt) |
| Instant noodles soup condiment-prescription A | 8.99 | 1.61 |
| Instant noodles (retail) | 77.36 | 13.82 |
| Water | 473.20 | 84.57 |
| Amount to | 559.55g | 100.00％ |
Table 37-1c: make things convenient for the preparation (estimating) of noodle soup by the taste taste panel
| Composition | Gram | Prescription % (wt/wt) |
| Instant noodles soup condiment-prescription A | 17.98 | 1.86 |
| Water | 946.40 | 98.14 |
| Amount to | 964.38g | 100.00％ |
Table 37-2a: make things convenient for noodle soup flavouring (MSG has reduced 66%)-prescription B
| Composition | Prescription % (wt/wt) |
| Salt (Morton Salt) | 35.07 |
| Sodium glutamate (Ajinomoto) | 5.71 |
| Hydrolyzed vegetable protein (Basic Food Flavors#C-303) | 5.85 |
| From dissolubility yeast extract (Sensient#945) | 0.88 |
| Ajitide?I+G(Ajinomoto) | 0.29 |
| Beans sauce powder (Nikken#5310) | 12.28 |
| Garlic powder (American Food Flavors, Inc #GA45) | 10.29 |
| Chicken powder (Henningson C-100-1B-AR #730) | 10.05 |
| Chicken flavouring (chicken flavor) (Mastertaste #F42X32) | 6.43 |
| Onion powder (Elite Spice #516) | 4.68 |
| Sugar, graininess (C﹠H) | 2.86 |
| Chicken cosmetics (powdered chicken Fat) (Henningson#732) | 2.81 |
| Turmeric (McCormick) | 1.17 |
| White pepper (Pacific Natural Spices) | 0.70 |
| The celery powder (Food Source, Inc#60) | 0.58 |
| Citric acid (ADM) | 0.35 |
| Amount to | 100％ |
Table 37-2b: make things convenient for the preparation (being prepared) of noodle soup with noodles
| Composition | Gram | Prescription % (wt/wt) |
| Instant noodles soup condiment-prescription B | 8.09 | 1.45 |
| Instant noodles (retail) | 77.36 | 13.85 |
| Water | 473.20 | 84.70 |
| Amount to | 558.65g | 100％ |
Table 37-2c: make things convenient for the preparation (estimating) of noodle soup by the taste taste panel
| Composition | Gram | Prescription % (wt/wt) |
| Instant noodles soup condiment-prescription B | 16.18 | 1.68 |
| Water | 946.40 | 98.32 |
| Amount to | 964.38g | 100.00％ |
Table 37-3a: make things convenient for noodle soup flavouring (MSG reduced 66% and contain flavour enhancer)-prescription C
| Composition | Prescription % (wt/wt) |
| Salt (Morton Salt) | 33.39 |
| The condiment concentrate (8.5ppm) that contains 0.1% compound 24 | 0.85 |
| The condiment concentrate (39.5ppm) that contains 0.1% compound 1 | 3.96 |
| Sodium glutamate (Ajinomoto) | 5.44 |
| Hydrolyzed vegetable protein (Basic Food Flavors#C-303) | 5.56 |
| From dissolubility yeast extract (Sensient#945) | 0.83 |
| Ajitide?I+G(Ajinomoto) | 0.28 |
| Beans sauce powder (Nikken#5310) | 11.69 |
| Garlic powder (American Food Flavors, Inc #GA45) | 9.79 |
| Chicken powder (Henningson C-100-1B-AR #730) | 9.57 |
| Chicken flavouring (chicken flavor) (Mastertaste #F42X32) | 6.12 |
| Onion powder (Elite Spice #516) | 4.45 |
| Sugar, graininess (C﹠H) | 2.73 |
| Chicken cosmetics (powdered chicken Fat) (Henningson#732) | 2.67 |
| Turmeric (McCormick) | 1.11 |
| White pepper (Pacific Natural Spices) | 0.67 |
| The celery powder (Food Source, Inc#60) | 0.56 |
| Citric acid (ADM) | 0.33 |
| Amount to | 100％ |
Table 37-3b: make things convenient for the preparation (being prepared) of noodle soup with noodles
| Composition | Gram | Prescription % (wt/wt) |
| Instant noodles soup condiment-prescription C | 8.49 | 1.52 |
| Instant noodles (retail) | 77.36 | 13.84 |
| Water | 473.20 | 84.64 |
| Amount to | 559.05 | 100％ |
Table 37-3c: make things convenient for the preparation (estimating) of noodle soup by the taste taste panel
*
| Composition | Gram | Prescription % (wt/wt) |
| Instant noodles soup condiment-prescription C | 16.98 | 1.76 |
| Water | 946.40 | 98.24 |
| Amount to | 968.38g | 100％ |
*Prescription 37-3a contains the combination of compound 24 and 1, and both are 1:4.5 finally making things convenient for the ratio in the noodle soup, are finally making things convenient in the noodle soup, and the ultimate density of compound 24 is 0.15ppm, and the ultimate density of compound 1 is 0.70ppm.
The sensory evaluation step:
The external testing person of 8 specialties is through training the relative intensity with the following taste characteristic of identification in the pairing contrast test: saline taste, delicate flavour/meat flavour, delicate flavour (umarni), broth-like flavor, bitter taste (bitter), aftertaste (linger) and peculiar smell (off flavor).The pairing contrast test is used to determine whether there is appreciable difference at two on taste between the sample of random-blind numbering.Each sample contains 2 ounces of noodle soup, and temperature is 120 ℉, and each group member carries out 5 pairing contrast tests altogether.
Estimate #1: the ability of distinguishing the delicate flavour of high MSG control formula and low MSG control formula
Purpose is to determine whether the group member can distinguish high MSG reference substance (full load amount MSG, prescription A) and MSG has reduced the difference on delicate flavour between 66% the reference substance (prescription B).
The result:
8 group members estimate 100% MSG instant noodles thick gravy to 33%MSG instant noodles thick gravy in the pairing contrast test, estimate 5 times.The result shows, it is brighter than 33% MSG instant noodles thick gravy that 25 evaluation results are classified as 100% MSG instant noodles thick gravy, and 15 evaluation results are to be classified as 33%MSG instant noodles thick gravy brighter.The result is referring to table 37-4.
Table 37-4:100%MSG instant noodles thick gravy is to 33%MSG instant noodles thick gravy
N=40 (8 group member * 5 time).
| Sample | Amount to |
| Select 100% MSG to make things convenient for noodle soup | 25 |
| Select 33% MSG to make things convenient for noodle soup | 15 |
| Amount to | 40 |
| Confidence level | 0.923 |
| Select 100% MSG to make things convenient for noodle soup (p value) | 0.077 |
Conclusion: the group member can distinguish 100% MSG and make things convenient for noodle soup MSG to be reduced 66% the noodle soup that makes things convenient for; And can correctly discern 100% MSG sample and obviously have more delicate flavour (p＜0.1) than 33% MSG instant noodles thick gravy.
Estimate #2: contrast high MSG make things convenient for noodle soup and prepare again contain compound 1 and 24 and MSG reduced by 66% soup
Purpose be measure the group member whether can distinguish high MSG noodle soup (full dose MSG, prescription A) with prepare again, MSG reduced between the noodle soup 66%, that contain 0.7ppm compound 1 and 0.15ppm compound 24 different on delicate flavour.
The result:
8 group members estimate 100% MSG and make things convenient for noodle soup to 33% MSG instant noodles thick gravy+0.15ppm compound 24 and 0.7ppm compound 1 in the pairing contrast experiment, repeat n=40 5 times.The result shows that 20 evaluation results think that 100% MSG makes things convenient for noodle soup brighter, and other 20 evaluation results think that 33% MSG+0.15ppm compound 24 and 0.70ppm compound 1 are brighter.The result is referring to table 37-5.
Table 37-5:100%MSG makes things convenient for noodle soup that 33%MSG+0.15ppm compound 24 and 0.7ppm compound 1 are made things convenient for noodle soup (n=40) (8 group member * 5 time).
| Sample | Amount to |
| Select 100% MSG to make things convenient for noodle soup | 20 |
| Select 33%MSG+0.15ppm compound 24 and 0.7ppm compound 1 instant noodles thick gravy | 20 |
| Amount to | 40 |
| Confidence level | <0.125 |
| Select 100% MSG to make things convenient for noodle soup (p-value) | >0.875 |
Conclusion:
The group member can not perception 100% MSG makes things convenient for noodle soup and 33% MSG+0.15ppm compound 24 and 0.7ppm compound 1 to make things convenient for significant difference (p＜0.1) on delicate flavour intensity between the noodle soup.Therefore, the consumption of MSG is significantly reduced, and uses Senomyx ' s reinforcing agent S336 and S807 to replace, on delicate flavour intensity without any change.
Only a few people among the experimenter also reports other sense of taste, after comprising employing compound 1 and 24, the saline taste of sample increases, in the sample that uses compound 1 and 24, the prolongation of delicate flavour holdup time has promoted the balance between the taste, and fragrant pungent, odoriferous herbs flavor and hot flavor are strengthened.Therefore, the use of compound mixture can reduce the consumption of MSG and other flavour enhancer such as IMP, GMP etc., thereby reduces cost.
Embodiment 38
MSG in the potato chips of replacement Cajun barbecue flavor
General introduction:
4 potato chips samples of preparation Cajun flavor compare by the test of people's taste.Do not contain MSG in a kind of contrast potato chips sample, contain 0.6% MSG that adds in the another kind of contrast potato chips sample, potato chips sample contains 3ppm embodiment 1 amide compound (form with the condiment concentrate composition adds), contains the embodiment 24 oxamides compounds (form with the condiment concentrate composition adds) of 3ppm in potato chips sample.In people's taste test group, 9 of 11 philtrums think personally that the fragrant peppery and pepper flavor of the Cajun of the potato chips sample that contains embodiment 1 and 24 compounds strengthens.Some group members report that the delicate flavour of the potato chips sample that contains embodiment 1 and 24 compounds increases.
The preparation of sample
By with embodiment 35 in identical two kinds of solid delicate flavour concentrate compositions of spray-drying step preparation of describing.Contain of compound, Neobee M-5 medium chain triglyceride, N-Lok 1930 modified food starch and the maltodextrin preparation of a kind of delicate flavour concentrate sample of 0.01% (wt/wt) embodiment, 1 compound by embodiment 1.The another kind of delicate flavour concentrate sample that contains 0.01% (wt/wt) embodiment, 24 compounds is similarly by embodiment 24 compounds, Neobee M-5 medium chain triglyceride, N-Lok 1930 modified food starch and maltodextrin preparation.
Utilize the kitchen auxiliary mixer, carrying out dry blend by ingredients listed among the his-and-hers watches 38-1 (mixed 5 minutes with 40-80rpm, use twisted wire mixing component (wire whip attachment)), preparation can make potato chips have the basic dry condiment mixture of Cajun flavor.
Table 38-1: dry condiment mixture-prescription A
| Composition | Gram | Prescription % (wt/wt) |
| Maltodextrin DE18 (Grain Processing Co.) | 29.33 | 29.33 |
| Salt powder (Morton) | 13.10 | 13.10 |
| Honey powder-50% honey (Mastertaste) | 27.37 | 27.37 |
| Onion powder (American Food Ingredients) | 7.16 | 7.16 |
| Garlic powder (American Food Ingredients) | 6.55 | 6.55 |
| Capsicum (McCormick) | 2.18 | 2.18 |
| Red pepper (McCormick) | 1.09 | 1.09 |
| The red pepper of Cayane (McCormick) that grinds | 0.71 | 0.71 |
| White pepper (McCormick) | 0.22 | 0.22 |
| Bitter orange powder (Mastertaste) | 4.58 | 4.58 |
| Pacify cool green pepper (McCormick) | 0.95 | 0.95 |
| The Semen Brassicae Campestris oil spraying | 0.87 | 0.87 |
| Tomato puree (McCormick) | 5.62 | 5.62 |
| Chardex?Hickory?MS(Red?Arrow) | 0.27 | 0.27 |
| Amount to | 100.00 | 100.00 |
General preparation method through the potato chips sample of seasoning:
Be fragmented into rationally uniform 1/2 ＂ x, 1/2 ＂ piece and be placed in the air-locked food bag of polyethylene 26.7cm x 27.9cm the fresh potato chips of Kettle (R) are manual.Then described potato chips were heated 20 seconds so that oil glows in 1200 watts of microwaves of AmanaCommercial, thereby condiment is bonded on the potato chips.Semen Brassicae Campestris oil is sprayed on the potato chips, then various condiment compositions (the condiment mixture of above-mentioned drying is with the MSG or the premixed of delicate flavour concentrate composition of any interpolation) is sprayed onto in the bag.Then sack was coated with described condiment mixture (table 2) in 1 minute equably with hand rolling on all potato chips.Before tasting potato chips are cooled to environment temperature (20 ℃/68 ℉).
Table 38-2: the Cajun barbecue flavor potato chips that do not contain MSG or delicate flavour concentrate composition
Table 38-3: the Cajun barbecue flavor potato chips that contain 0.6%MSG
Table 38-4: the Cajun barbecue flavor potato chips that contain 3ppm compound 1
Table 38-5: the Cajun barbecue flavor potato chips that contain 3ppm compound 24
The sensory evaluation step:
11 external testing persons are through training to discern the relative intensity of following taste characteristic: sweet taste, saline taste, delicate flavour/meat flavour, delicate flavour (umarni), broth-like flavor, bitter taste (bitter), aftertaste (linger) and peculiar smell (offflavors).The group member has estimated four kinds of sample types of Cajun barbecue flavor potato chips in (the FocuS Group) of group's informal discussion form flavor tests step, and be required to write down evaluation to following some characteristics: sweet taste, barbecue flavor, the fragrant pungent of Cajun, pepper flavor, onion flavor, saline taste, potato flavor, delicate flavour (umami), peculiar smell and other taste, and whether evaluation is liked or is disliked.And be required to estimate difference and possibility aspect taste and taste enhancing on the delicate flavour.
The result:
In general, 9/11 group member reports that the sample that contains compound 1 and 24 has fragrant pungent of stronger Cajun and pepper flavor.
Embodiment 39
Replace the MSG in the Pizza sauce
General introduction:
Preparation contains the water soluble condiment concentrate composition of embodiment 1 compound, with the MSG in its replacement Pizza sauce (pizza sauce), by the test of people's taste itself and the Pizza sauce that contains full dose MSG is compared then.Most of testers can not distinguish the taste between them.
The water soluble condiment concentrate composition that contains compound 1:
In order to be formulated into effectively in the Pizza sauce, compound 1 is dissolved in the water soluble delicate flavour condiment concentrate composition that preparation in the propane diols contains 0.1% compound 1.
Take by weighing the 18221.7600g propane diols (by Gold Coast, Inc. provide) be placed in the 2000ml stainless steel cylinder, digesting compound 1 with Silverson Mill (L4RT type) (described Silverson Mill has square opening high shear sieve and is arranged on 2000rmp) with 18.2400 slowly is added in the 700.00g propane diols, all be added in the propane diols up to all dry S807 (compound 1), the rotating speed of mill is increased to 5,000-6,000rpm continues 8-10 minute.With remaining 17,521.76g propane diols places 10 gallons of steam jacket kettles that are equipped with Lightnin blender (utilizing three impellers), be heated to 50 ℃ (120 ℉), then the solution through grinding slowly be added in the propane diols through adding thermal agitation that is contained in the kettle.The heating mixing lasts 30 minutes and dissolves fully up to compound 1, then solution is cooled to 80 ℉, then with the Unispense plugger 62 gram liquid delicate flavour condiment is filled in the 2oz glass container of sterilization, stores.The water activity of solution (water activity) is 0.953@24.7 ℃, and refractive index is 1.4328, and the ultimate density of this delicate flavour condiment is for containing 0.10% compound 1.The analysis showed that through HPLC the average recovery rate of compound 1 is 94% of a theoretical value.
The preparation process of Pizza sauce:
Adopt following table 39-1 and 39-2 ingredients listed to utilize two kinds of Pizza sauce samples of following step preparation, a kind of MSG of 0.4% that contains does not a kind ofly contain MSG but contains 1.1ppm compound 1.
With salt, citric acid, sugar, spice and odoriferous herbs comprise MSG in advance with solid form with 80-100rpm blend in 6 quarts of bowls, utilize kitchen auxiliary mixer to mix 5 minutes with mixing component (whip attachment).Water is placed clean kettle, stir with 120-200rpm with the Lightnin blender and form whirlpool.Xiang Shuizhong slowly adds 0.10% delicate flavour and forms compound 1, mixes 5 minutes.Continue to carry out with 80-100rpm at blender slowly to add vinegar and solid spice mixture under the condition of blend, the flavouring dissolving up to drying needs about 5 minutes.Add tomato puree, slurries were mixed 10 minutes again.Gained Pizza sauce is transferred to the 6 quarts of pots of stainless steel that place on the gas burner, be heated to pasteurizing temperature (175-190 ℉), the shortest keeping 2 minutes is cooled to environment temperature (70+/-2 ℉).
Table 39-1: the contrast Pizza sauce that contains sodium glutamate
| Composition | Gram | Prescription % (wt/wt) |
| Water | 252.75 | 50.55 |
| Tomato puree (the Ralphs 5TP1Q of retail) | 220.80 | 44.16 |
| Salt (Morton Salt) | 9.00 | 1.80 |
| Sugar (C﹠H#801461) | 7.95 | 1.59 |
| 50 of distilled vinegars (Heinz HF6A06UW) | 3.75 | 0.75 |
| Sodium glutamate (Ajinomoto 310704) | 2.00 | 0.40 |
| Black pepper 28 orders (Pacific Spice SA#01406) | 1.05 | 0.21 |
| Onion powder (Pacific Spice SA#C1406) | 0.70 | 0.14 |
| Garlic powder (American Ingredients GA45) | 0.70 | 0.14 |
| Citric acid (ADM S501132) | 0.70 | 0.14 |
| The wild marjoram (oregano) (McCormick 523561) that grinds | 0.45 | 0.09 |
| Purple perilla (Basil) (McCormick 526961) | 0.15 | 0.03 |
| Amount to | 500 | 100 |
| Analyze | ||
| pH | 3.92 | |
| %TA (with the titrable acidity of acetometer) | 0.72 | |
| Brix Scale | 16.72 |
Table 39-2: contain 1.10ppm compound 1 but do not contain the Pizza sauce of MSG
| Composition | Gram | Prescription % (wt/wt) |
| Water | 253.58 | 50.72 |
| Tomato puree (the Ralphs 5TP1Q of retail) | 220.80 | 44.16 |
| Salt (Morton Salt) | 9.625 | 1.93 |
| Sugar (C﹠H#801461) | 7.95 | 1.59 |
| 50 of distilled vinegars (Heinz) | 3.75 | 0.75 |
| Black pepper 28 orders (Pacific Spice SA#01406) | 1.05 | 0.21 |
| Onion powder (Pacific Spice SA#C1406) | 0.70 | 0.14 |
| Garlic powder (American Ingredients GA45) | 0.70 | 0.14 |
| Citric acid (ADM S501132) | 0.70 | 0.14 |
| The concentrate that contains 0.10% compound 1 | 0.55 | 0.11 |
| The wild marjoram (oregano) (McCormick 523561) that grinds | 0.45 | 0.06 |
| Purple perilla (Basil) (McCormick 526961) | 0.15 | 0.03 |
| Amount to | 500 | 100 |
| Analyze | ||
| pH | 3.75 | |
| ％TA | 0.80 | |
| Brix Scale | 16.10 |
Sensory evaluation:
10 professional flavor tests persons are through training to discern the relative intensity of following taste characteristic: saline taste, delicate flavour/meat flavour, delicate flavour (umarni), broth-like flavor, bitter taste (bitter), aftertaste (linger) and peculiar smell (offflavors).Triangle difference experiment (triangle difference test) can be measured the difference that whether has between two products on the delicate flavour.Provide three blind numberings, chance sample to the group member.Two samples are identical, and one is different.In order to experimentize exactly, the group member need taste all these three samples and can correctly point out and other two different samples.
The sample of ignorant of the economics numbering provides with form at random.Every group member will carry out 2 triangle experiments (triangle test) altogether, tests 3 samples at every turn.
A. test 1:2 sample and contain 1.1ppm compound 1; A sample contains MSG.
B. test 2:2 sample and contain MSG; A sample contains 1.1ppm compound 1.
Table 39-3: triangle experimental result (n=20) (10 group member * 2 time)
| Sample | Experiment 1 | Experiment 2 | Amount to |
| Incorrect number of times | 7 | 4 | 11 |
| Correct number of times | 3 | 6 | 9 |
| Amount to | 10 | 10 | 20 |
| Conspicuousness (p-value) | 0.701 | 0.077 | 0.191 |
The experiment #1 in, among 10 group members only 3 correctly discerned different sample (sample that promptly contains MSG).In experiment #2, correctly discerned different sample (sample that promptly contains compound 1) for 6 among 10 group members.In testing for 20 times altogether, different samples has correctly been discerned in 9 experiments.
Those skilled in the art know that to be understood that, can modify and change the present invention without departing from the scope and spirit of the present invention.On the basis of the embodiment of specification of the present invention and disclosure, other embodiment of the present invention it will be apparent to those skilled in the art that.Specification of the present invention and embodiment only are used for the present invention is carried out exemplary explanation, and actual range of the present invention is as described in claims.
Claims (189)
1. method for preparing the solid seasoning concentrate composition comprises:
A) provide one or more amide compounds or its one or more edible salts with following structural formula:
Wherein
I) A is 5 or 6 yuan of aryl or heteroaryl,
Ii) m is 0,1,2,3 or 4,
Iii) each R
1 'Be independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
Iv) R
2Have 3 to 15 carbon atoms, and be branched alkyl, cycloalkyl or heterocyclic radical, described group randomly replaces through 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
B) described one or more amide compounds or its edible salts are dissolved in one or more edible liquid, form condiment solution;
C) described condiment solution is contacted with one or more edible solid carriers or its solution, dispersion liquid or emulsion, form midbody composite; With
D) liquid is removed or made liquid from described midbody composite, scatter and disappear from described midbody composite, form the solid seasoning concentrate composition.
2. the process of claim 1 wherein that its step of scattering and disappearing is removed or made to liquid is drying steps.
3. the method for claim 2, wherein said drying steps comprises spray-drying.
4. the method for claim 2, wherein said drying steps comprises evaporation.
5. the method for claim 2, wherein said drying steps comprises heating.
6. the process of claim 1 wherein that described contact procedure comprises makes described condiment solution with described one or more edible solid carriers or its solution, dispersion liquid or emulsion homogenizing.
7. the process of claim 1 wherein that A is a phenyl.
8. claim 1 or 7 method, wherein each R
1 'Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, CN, NH
2, NHCH
3, N (CH
3)
2, COOCH
3, SCH
3, SCH
2CH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
9. claim 1 or 7 method, wherein R
2Substituting group is selected from hydrogen, hydroxyl, fluorine, chlorine, CN, NH
2, NHCH
3, N (CH
3)
2, COOCH
3, SCH
3, SCH
2CH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
10. claim 1 or 7 method, wherein R
2Be branched alkyl.
11. the process of claim 1 wherein that described amide compound has following structural formula:
Or
R wherein
1a, R
1a 'And R
1bBe hydrogen or low alkyl group independently.
12. the method for claim 11, wherein R
1a, R
1a 'And R
1bBe hydrogen.
13. the method for claim 11, wherein R
2For having the branched alkyl of 3 to 10 carbon atoms.
14. the process of claim 1 wherein that described amide compound has following structural formula:
15. each method among claim 1 and the 7-16, the amount of wherein said one or more amide compounds in described solid seasoning concentrate composition are about 100 to about 100,000ppm.
16. the process of claim 1 wherein that described solid seasoning concentrate composition also contains at least a following component that is selected from: sodium glutamate, inosine monophosphate, guanosine monophosphate, from dissolubility yeast extract, hydrolyzed vegetable protein or their mixture.
17. the process of claim 1 wherein that described solid seasoning concentrate composition contains sodium glutamate.
18. the process of claim 1 wherein that described one or more edible liquid comprise water.
19. the process of claim 1 wherein that described one or more edible liquid comprise ethanol, propane diols, glycerine, glyceryl triacetate or their mixture.
20. the process of claim 1 wherein that described one or more edible liquid comprise one or more edible oils or one or more edible triglycerides.
21. the process of claim 1 wherein that described one or more edible liquid comprise following one or more: benzylalcohol, glyceryl triacetate, triethyl citrate and Ergol.
22. the process of claim 1 wherein that described one or more edible solid carriers comprise the edible polysaccharide.
23. the process of claim 1 wherein that described one or more edible solid carriers comprise plant powder or plant extracts.
24. the process of claim 1 wherein that described one or more edible solid carriers comprise following one or more: A type gelatin, the Type B gelatin, Quadrafos, alginates, shitosan, carrageenan, pectin, starch, Arabic gum, ALA, beta lactoglobulin, ovalbumin, polysorbate, cyclodextrin, cellulose, methylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, milk powder, lactoprotein, lactalbumin, soybean protein, rape albumen, albumin, the gelatin that Jewish canon be can't help, the gelatin that Jewish canon is forbidden, the gelatin that gelatin that islamic canon be can't help and islamic canon are forbidden.
25. the process of claim 1 wherein that described one or more edible solid carriers comprise maltodextrin.
26. the process of claim 1 wherein that described one or more edible solid carriers comprise modified starch.
27. the process of claim 1 wherein that described one or more edible solid carriers comprise Arabic gum.
28. solid seasoning concentrate composition by each method preparation in the aforementioned claim.
29. a method for preparing the solid seasoning concentrate composition comprises:
A) provide one or more oxamides compounds or its one or more edible salts with following structural formula:
Wherein
I) A and B are aryl, heteroaryl, cycloalkyl or heterocyclic radical independently, and described group contains 5 to 12 annular atomses,
Ii) m and n are 0,1,2,3 or 4-8 independently,
Iii) R
70And R
80Be independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical, and R
9And R
10Be independently selected from H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl and C
1-C
6Thiazolinyl, or two R
70Form the (methylenedioxy) basic ring together;
B) described one or more oxamides compounds or its edible salts are dissolved in one or more edible liquid, form condiment solution;
C) described condiment solution is contacted with one or more edible solid carriers or its solution, dispersion liquid or emulsion, form midbody composite; With
D) from described midbody composite, remove or make liquid from described midbody composite, to evaporate liquid, form the solid seasoning concentrate composition.
30. the method for claim 29, the step of wherein liquid being removed or made its evaporation is a drying steps.
31. the method for claim 30, wherein said drying steps comprises spray-drying.
32. the method for claim 30, wherein said drying steps comprises evaporation.
33. the method for claim 30, wherein said drying steps comprises heating.
34. comprising, the method for claim 29, wherein said contact procedure make described condiment solution with described one or more edible solid carriers or its solution, dispersion liquid or emulsion homogenizing.
35. the method for claim 29, wherein A comprises phenyl.
36. the method for claim 29, wherein B comprises the optional pyridine radicals that is substituted.
37. the method for claim 29, wherein A is a phenyl, and B is a pyridine radicals.
38. the method for claim 29, wherein R
70And R
80Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
39. the method for claim 29, wherein said one or more oxamides compounds comprise the compound with following structural formula:
40. the method for claim 29, wherein said one or more oxamides compounds comprise the compound with following structural formula:
41. the method for claim 29, wherein said one or more oxamides compounds comprise the compound with following structural formula:
42. the method for claim 29, the amount of wherein said one or more amide compounds in described solid seasoning concentrate composition are about 100 to about 100,000ppm.
43. the method for claim 29, wherein said solid seasoning concentrate composition contains at least a following component: sodium glutamate, inosine monophosphate, guanosine monophosphate, from dissolubility yeast extract, hydrolyzed vegetable protein or their mixture.
44. the method for claim 29, wherein said solid seasoning concentrate composition contains sodium glutamate.
45. the method for claim 29, wherein said one or more edible liquid comprise water.
46. the method for claim 29, wherein said one or more edible liquid comprise ethanol, propane diols, glycerine or their mixture.
47. the method for claim 29, wherein said one or more edible liquid comprise one or more edible oils or one or more edible triglycerides.
48. the method for claim 29, wherein said one or more edible liquid comprise following one or more: benzylalcohol, glyceryl triacetate, triethyl citrate and Ergol.
49. the method for claim 29, wherein said one or more edible solid carriers comprise plant powder or plant extracts.
50. the method for claim 29, wherein said one or more edible solid carriers comprise the edible polysaccharide.
51. the method for claim 29, wherein said one or more edible solid carriers comprise following one or more: A type gelatin, the Type B gelatin, Quadrafos, alginates, shitosan, carrageenan, pectin, starch, Arabic gum, ALA, beta lactoglobulin, ovalbumin, polysorbate, cyclodextrin, cellulose, methylcellulose, ethyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, milk powder, lactoprotein, lactalbumin, soybean protein, rape albumen, albumin, the gelatin that Jewish canon be can't help, the gelatin that Jewish canon is forbidden, the gelatin that gelatin that islamic canon be can't help and islamic canon are forbidden.
52. the method for claim 29, wherein said one or more edible solid carriers comprise maltodextrin.
53. the method for claim 29, wherein said one or more edible solid carriers comprise modified starch.
54. the method for claim 29, wherein said one or more edible solid carriers comprise Arabic gum.
55. the method for claim 29, the amount of wherein said one or more edible solid carriers in described solid seasoning concentrate composition is about 75% to about 90% of composition total weight.
56. solid seasoning concentrate composition by each method preparation among the claim 29-55.
57. a method for preparing lipophilicity delicate flavour condiment concentrate composition comprises:
A) one or more edible fats or oil are contacted with one or more amide compound or its one or more edible salts with following structural formula, form precursor condiment mixture:
Wherein
I) A is 5 or 6 yuan of aryl or heteroaryl,
Ii) m is 0,1,2,3 or 4,
Iii) each R
1' be independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
Iv) R
2Have 3 to 15 carbon atoms, and be branched alkyl, cycloalkyl or heterocyclic radical, described group randomly replaces through 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
B) the described precursor condiment mixture of processing forms lipophilicity delicate flavour condiment concentrate composition, and wherein most at least described one or more amide compounds or its edible salts exist with that disperse and form undissolved particulate.
58. the method for claim 57, wherein said procedure of processing comprises homogenizing or grinding.
59. the method for claim 57, the average grain diameter of wherein said undissolved particulate is less than about 100 microns.
60. the method for claim 57, wherein A is a phenyl.
61. the method for claim 57 or 59, wherein each R
1 'Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, CN, NH
2, NHCH
3, N (CH
3)
2, COOCH
3, SCH
3, SCH
2CH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
62. the method for claim 57 or 59, wherein the R2 substituting group is selected from hydrogen, hydroxyl, fluorine, chlorine, CN, NH
2, NHCH
3, N (CH
3)
2, COOCH
3, SCH
3, SCH
2CH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
63. the method for claim 57 or 59, wherein R
2Be branched alkyl.
64. the method for claim 57, wherein said amide compound has following structural formula:
R wherein
1a, R
1a 'And R
1bBe hydrogen or low alkyl group independently.
65. the method for claim 64, wherein R
1a, R
1a 'And R
1bBe hydrogen.
66. the method for claim 64, wherein R
2For having the branched alkyl of 3-10 carbon atom.
67. the method for claim 57, wherein said amide compound has following structural formula:
68. a method for preparing lipophilicity delicate flavour condiment concentrate composition comprises:
A) one or more edible fats or oil are contacted with one or more oxamides compound or its one or more edible salts with following structural formula, form precursor condiment mixture:
Wherein
I) A and B are aryl, heteroaryl, cycloalkyl or heterocyclic radical independently, and described group contains 5-12 annular atoms,
Ii) m and n are 0,1,2,3 or 4-8 independently,
Iii) R
70And R
80Be independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical, and R
9And R
10Be independently selected from H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl and C
1-C
6Thiazolinyl, or two R
70Form together the (methylenedioxy) basic ring and
B) the described precursor condiment mixture of processing forms lipophilicity delicate flavour condiment concentrate composition, and wherein most at least described one or more amide compounds or its edible salts exist with that disperse and form undissolved particulate.
69. the method for claim 68, wherein said procedure of processing comprises homogenizing or grinding.
70. the method for claim 68, wherein said undissolved particulate has less than about 100 microns average grain diameter.
71. the method for claim 68, wherein A comprises phenyl.
72. the method for claim 68, wherein B comprises the optional pyridine radicals that is substituted.
73. the method for claim 68, wherein A is a phenyl, and B is a pyridine radicals.
74. the method for claim 68, wherein R
70And R
80Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
75. the method for claim 68, wherein said one or more oxamides compounds comprise the compound with following structural formula:
76. the method for claim 68, wherein said one or more oxamides compounds comprise the compound with following structural formula:
77. the method for claim 68, wherein said one or more oxamides compounds comprise the compound with following structural formula:
78. a method for preparing liquid delicate flavour condiment concentrate composition comprises:
A) mix following substances i with any order), ii) and iii), form and contain at least about following one or more amide compounds of 10ppm or the liquid delicate flavour condiment concentrate composition of its edible salts:
I) contain the liquid phase of one or more edible solvents, described solvent is selected from benzylalcohol, triethyl citrate, Ergol, glyceryl triacetate, glycerine, propane diols or its methyl ether or ethylether or its acetate,
Ii) sodium glutamate or glutamic acid and
Iii) one or more have amide compound or its one or more edible salts of following structural formula:
Wherein
(1) A is 5 or 6 yuan of aryl or heteroaryl,
(2) m is 0,1,2,3 or 4,
(3) each R
1 'Be independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
(4) R
2Have 3-15 carbon atom, and be branched alkyl, cycloalkyl or heterocyclic radical, described group randomly replaces through 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group.
79. the method for claim 78, wherein said liquid delicate flavour condiment concentrate composition contain the 10ppm that has an appointment to about 10, described one or more amide compounds or its edible salts of 000ppm.
80. the method for claim 78, wherein said liquid delicate flavour condiment concentrate composition also contains water.
81. the method for claim 78, the total mole number of wherein said sodium glutamate or glutamic acid is that about 5:1 is to about 1000:1 divided by the mol ratio of the total mole number of described one or more amide compounds.
82. the method for claim 78, wherein A is a phenyl.
83. the method for claim 78 or 82, wherein each R
1 'Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, CN, NH
2, NHCH
3, N (CH
3)
2, COOCH
3, SCH
3, SCH
2CH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
84. the method for claim 78 or 82, wherein R
2Substituting group is selected from hydrogen, hydroxyl, fluorine, chlorine, CN, NH
2, NHCH
3, N (CH
3)
2, COOCH
3, SCH
3, SCH
2CH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
85. the method for claim 78 or 82, wherein R
2Be branched alkyl.
86. the method for claim 82, wherein said amide compound has following structural formula:
R wherein
1a, R
1a 'And R
1bBe hydrogen or low alkyl group independently.
87. the method for claim 86, wherein R
1a, R
1a 'And R
1bBe hydrogen.
88. the method for claim 82, wherein R
2For having the branched alkyl of 3-10 carbon atom.
89. the method for claim 82, wherein said amide compound has following structural formula:
90. liquid delicate flavour condiment concentrate composition by the preparation of the method for claim 78.
91. a method for preparing liquid delicate flavour condiment concentrate composition comprises:
A) mix following substances i with any order) and ii), form and contain at least about following one or more amide compounds of 10ppm or the liquid delicate flavour condiment concentrate composition of its edible salts:
I) contain the liquid phase of one or more edible solvents, described solvent is selected from benzylalcohol, triethyl citrate, Ergol, glyceryl triacetate, glycerine, propane diols or its methyl ether or ethylether or its acetate,
Ii) sodium glutamate or glutamic acid and one or more have oxamides compound or its one or more edible salts of following structural formula:
Wherein
(1) A and B are aryl, heteroaryl, cycloalkyl or heterocyclic radical independently, and described group contains 5 to 12 annular atomses,
(2) m and n are 0,1,2,3 or 4-8 independently,
(3) R
70And R
80Be independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical, and R
9And R
10Be independently selected from H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl and C
1-C
6Thiazolinyl, or two R
70Form the (methylenedioxy) basic ring together.
92. the method for claim 91, wherein said liquid delicate flavour condiment concentrate composition contain the 10ppm that has an appointment to about 10, described one or more amide compounds or its edible salts of 000ppm.
93. the method for claim 91, wherein said liquid delicate flavour condiment concentrate composition also contains water.
94. the method for claim 91, the total mole number of wherein said sodium glutamate or glutamic acid is that about 5:1 is to about 1000:1 divided by the mol ratio of the total mole number of described one or more amide compounds.
95. the method for claim 91, wherein A comprises phenyl.
96. the method for claim 91, wherein B comprises the optional pyridine radicals that is substituted.
97. the method for claim 91, wherein A is a phenyl, and B is a pyridine radicals.
98. the method for claim 91, wherein R
70And R
80Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
99. the method for claim 91, wherein said oxamides compound has following structural formula:
100. the method for claim 91, wherein said oxamides compound has following structural formula:
The method of claim 91, wherein said oxamides compound has following structural formula:
A kind of method that sodium content in delicate flavour soup, meat soup, clear soup, tartar sauce or the thick gravy that contains sodium chloride and sodium glutamate is reduced comprises:
A) prepare existing soup, meat soup, clear soup, tartar sauce, thick gravy or their precursor substance again, make it contain the amide compound with following structural formula or its one or more edible salts at least about 0.01ppm:
Wherein
(i) A is 5 or 6 yuan of aryl or heteroaryl,
(ii) m is 0,1,2,3 or 4,
(iii) each R
1 'Be independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
(iv) R
2Have 3-15 carbon atom, and be branched alkyl, cycloalkyl or heterocyclic radical, described group is optional to be replaced through 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group and
B) amount of one or more sodium salts in soup, meat soup, clear soup, tartar sauce or the thick gravy that is added to described preparation is again reduced, compare with existing soup, meat soup, clear soup, tartar sauce or thick gravy, the amount of sodium salt is reduced by at least about 5%.
The method of claim 102, wherein the most of people in the group that is made up of at least 8 famous person's flavor tests persons can not distinguish the salt content in salt content and soup, meat soup, clear soup, tartar sauce or the thick gravy buied in soup, meat soup, clear soup, tartar sauce or the thick gravy of described preparation again.
The method of claim 102, the amount that wherein is added to the sodium in soup, meat soup, clear soup, tartar sauce or the thick gravy that contains described amide compound is compared with existing soup, meat soup, clear soup, tartar sauce or thick gravy and is reduced by at least about 10wt%.
The method of claim 102, the concentration of wherein said amide compound in soup, meat soup, clear soup, tartar sauce or the thick gravy of described preparation again is about 0.1 to about 2ppm.
The method of claim 102 wherein is added to potassium chloride in soup, meat soup, clear soup, tartar sauce or the thick gravy of described preparation again.
The method of claim 102, wherein A is a phenyl.
The method of claim 102, wherein each R
1 'Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, CN, NH
2, NHCH
3, N (CH
3)
2, COOCH
3, SCH
3, SCH
2CH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
The method of claim 102, wherein each R
2Substituting group is independently selected from hydrogen, hydroxyl, fluorine, chlorine, CN, NH
2, NHCH
3, N (CH
3)
2, COOCH
3, SCH
3, SCH
2CH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
110. the method for claim 102, wherein R
2Be branched alkyl.
111. the method for claim 110, wherein said amide compound has following structural formula:
R wherein
1a, R
1a 'And R
1bBe hydrogen or low alkyl group independently.
112. the method for claim 111, wherein R
1a, R
1a 'And R
1bBe hydrogen.
113. the method for claim 111, wherein R
2For having the branched alkyl of 3-10 carbon atom.
114. the method for claim 111, wherein said amide compound has following structural formula:
115. the soup of preparation again by each method preparation among the claim 102-114.
116. the method that the sodium content in delicate flavour soup, meat soup, clear soup, tartar sauce or the thick gravy that contains sodium chloride and sodium glutamate is reduced comprises:
A) prepare existing soup, meat soup, clear soup, tartar sauce, thick gravy or their precursor substance again, it contained at least about one or more of 0.01ppm have oxamides compound or its one or more edible salts of following structural formula:
Wherein
(1) A and B are aryl, heteroaryl, cycloalkyl or heterocyclic radical independently, and described group contains 5 to 12 annular atomses,
(2) m and n are 0,1,2,3 or 4-8 independently,
(3) R
70And R
80Be independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical, and R
9And R
10Be independently selected from H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl and C
1-C
6Thiazolinyl, or two R
70Form the (methylenedioxy) basic ring together; With
B) amount of one or more sodium salts in soup, meat soup, clear soup, tartar sauce or the thick gravy that is added to described preparation is again reduced, compare with existing soup, meat soup, clear soup, tartar sauce or thick gravy, the amount of sodium salt is reduced by at least about 5%.
117. the amount of the sodium in the method for claim 116, the amount that wherein is added to the sodium in described soup, meat soup, clear soup, tartar sauce or the thick gravy that contains described amide compound and existing soup, meat soup, clear soup, tartar sauce or thick gravy is compared and is reduced by at least about 10wt%.
118. the method for claim 116 wherein is added to potassium chloride in soup, meat soup, clear soup, tartar sauce or the thick gravy of described preparation again.
119. the method for claim 116, the concentration of wherein said amide compound in soup, meat soup, clear soup, tartar sauce or the thick gravy of described preparation again is about 0.1 to about 2ppm.
120. the method for claim 116, wherein A comprises phenyl.
121. the method for claim 116, wherein B comprises the optional pyridine radicals that is substituted.
122. the method for claim 116, wherein A comprises phenyl, and B comprises pyridine radicals.
123. the method for claim 116, wherein R
70And R
80Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
124. the method for claim 116, wherein said oxamides compound has following structural formula:
125. the method for claim 116, wherein said oxamides compound has following structural formula:
126. the method for claim 116, wherein said oxamides compound has following structural formula:
127. a method that makes N-(heptan-4-yl)-benzo [d] [1,3] dioxole-5-formamide crystallization comprises:
A) will contain N-(heptan-4-yl)-benzo [d] [1,3] dioxole-composition of 5-formamide at high-temperature digestion in ethyl acetate and heptane, form solution; With
B) cool off described solution, form the solid contain N-(heptan-4-yl)-benzo [d] [1,3] dioxole-5-formamide.
128. being purity, the method for claim 127, wherein said solid be higher than 99% N-(heptan-4-yl)-benzo [d] [1,3] dioxole-5-formamide.
129. a method for preparing 2-methoxyl group-4-methyl-benzylamine or its salt comprises:
A) with methylating reagent 2-hydroxy-4-methyl-benzamide is methylated, obtain 2-methoxyl group-4-methyl-benzamide; With
B) with hydride reducer 2-methoxyl group-4-methyl-benzamide is reduced, obtain 2-methoxyl group-4-methyl-benzylamine or its salt.
130. a method for preparing 2-(5-picoline-2-yl) ethamine or its salt comprises:
A) handle acetonitrile with highly basic, make hydrogen ion from wherein leaving away;
B) make 2-bromo-5-picoline and described acetonitrile condensation, obtain 2-(5-picoline-2-yl) acetonitrile through alkali treatment; With
C) cyano group to 2-(5-picoline-2-yl) acetonitrile reduces, and obtains 2-(5-picoline-2-yl) ethamine or its salt.
131. being the lithium salts with lithium alkylide or aryl lithium or dialkylamine, the method for claim 130, wherein said treatment step carry out.
132. being included under the existence of catalyst, the method for claim 130, wherein said reduction step carry out hydrogenation.
133. the method for claim 132, wherein said catalyst are Raney Ni.
134. one kind prepares N
1-(2-methoxyl group-4-methyl-benzyl)-N
2The method of-(2-(5-picoline-2-yl) ethyl) oxamides comprises:
A) make the reaction of 2-methoxyl group-4-methylbenzylamine and 2-chloro-oxo acetic acid esters, obtain N-(2-methoxyl group-4-methyl-benzyl)-oxalic acid acid amides ethyl ester; With
B) make the reaction of N-(2-methoxyl group-4-methyl-benzyl)-oxalic acid acid amides ethyl ester and 2-(5-picoline-2-yl) ethamine, obtain N
1-(2-methoxyl group-4-methyl-benzyl)-N
2-(2-(5-picoline-2-yl) ethyl) oxamides.
135. the method for claim 134, wherein said step (b) is to carry out in the presence of acetonitrile and triethylamine.
136. an edible composition contains:
A) one or more of delicate flavour regulated quantity have amide compound or its one or more edible salts of following structural formula:
Wherein
(i) A ' is 5 or 6 yuan of aryl or heteroaryl,
(ii) m is 0,1,2,3 or 4,
(iii) each R
1 'Be independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group, one or two R
1 'Substituting group is bonded together, form saturated alkylenedioxy group and
(iv) R
2Have 3-15 carbon atom, and be branched alkyl, cycloalkyl or heterocyclic radical, described group is optional to be replaced through 1,2,3 or 4 substituting group, and described substituting group is independently selected from hydroxyl, NH
2, SH, halogen and C
1-C
4Organic group; With
B) one or more of delicate flavour regulated quantity have oxamides compound or its one or more edible salts of following structural formula:
Wherein
(i) A and B are aryl, heteroaryl, cycloalkyl or heterocyclic radical independently, and described group contains 5 to 12 annular atomses,
(ii) m and n are 0,1,2,3 or 4-8 independently,
(iii) R
70And R
80Be independently selected from hydrogen, alkyl, alkoxyl, alkoxyl-alkyl, OH, SR
9, halogen, CN, NO
2, CO
2R
9, COR
9, CONR
9R
10, NR
9R
10, NR
9COR
10, SOR
9, SO
2R
9, SO
2NR
9R
10, NR
9SO
2R
10, thiazolinyl, cycloalkyl, cycloalkenyl group, aryl, heteroaryl and heterocyclic radical, and R
9And R
10Be independently selected from H, C
1-C
6Alkyl, C
3-C
6Cycloalkyl and C
1-C
6Thiazolinyl, or two R
70Form the (methylenedioxy) basic ring together.
137. the composition of claim 136, it also contains sodium glutamate.
138. the composition of claim 136, it contains described one or more amide compounds of 0.1 to 3ppm and described one or more oxamides compounds of 0.1 to 3ppm.
139. the composition of claim 136, wherein said edible composition are clear soup, meat soup or soup.
140. the composition of claim 136, wherein said edible composition are tartar sauce or flavouring.
141. the composition of claim 136, wherein said edible composition are vegetable juice or tomato juice.
142. the composition of claim 136, wherein said edible composition are salad dressing or mayonnaise.
143. the composition of claim 136, wherein said edible composition are the delicate flavour flavoring compositions.
144. the composition of claim 136, wherein said edible composition is stuck with paste fried food for hanging.
145. the composition of claim 136, wherein said edible composition are the condiment concentrate composition.
146. the composition of claim 145, wherein said condiment concentrate composition contains 10 to 10, described one or more amide compounds or the oxamides compound of 000ppm.
147. the composition of claim 145, wherein said condiment concentrate composition is a fluid composition.
148. the composition of claim 145, wherein said condiment concentrate composition is a solid composite.
149. the composition of claim 148, wherein said solid composite prepares by method for congregating.
150. the composition of claim 148, wherein said solid composite prepares by dry blend.
151. the composition of claim 136, wherein A ' is a phenyl, and each R
1 'Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, CN, NH
2, NHCH
3, N (CH
3)
2, COOCH
3, SCH
3, SCH
2CH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
152. the composition of claim 151, wherein R
2For having the branched alkyl of 3-10 carbon atom.
153. the composition of claim 136, wherein said amide compound has following structural formula:
R wherein
1a, R
1a 'And R
1bBe hydrogen or low alkyl group independently.
154. the composition of claim 136, wherein said amide compound has following structural formula:
155. the composition of claim 136, wherein A is a phenyl, and B is a pyridine radicals.
156. the composition of claim 155, wherein R
70And R
80Be independently selected from hydrogen, hydroxyl, fluorine, chlorine, NH
2, NHCH
3, N (CH
3)
2, CO
2CH
3, SCH
2CH
3, SCH
3, methyl, ethyl, isopropyl, vinyl, trifluoromethyl, methoxyl group, ethyoxyl, isopropoxy and trifluoromethoxy.
157. the composition of claim 136, wherein said one or more oxamides compounds have following structural formula:
158. the composition of claim 157, wherein said amide compound has following structural formula:
159. the composition of claim 158, it also contains sodium glutamate.
160. a method for preparing N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides with following structural formula comprises:
A) in the presence of tertiary amine base and solvent or solvent mixture, make 2,4-dimethoxybenzylamine or its salt and the condensation of 2-chloro-2-oxo acetic acid esters, described solvent or solvent mixture comprise following one or more: toluene, ortho-xylene, meta-xylene, paraxylene and nitrobenzene, and described 2-chloro-2-oxo acetic acid esters has following structural formula:
Formation has the solution of 2-(2,4-dimethoxy-benzyl the amino)-2-oxo acetic acid esters of following structural formula:
Wherein R is C
1-C
4The straight or branched alkyl; With
B) solution of described 2-(2,4-dimethoxy-benzyl the amino)-2-oxo acetic acid esters that forms in step (a) and 2-(pyridine-2-yl) ethamine with following structural formula are reacted:
Form N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides.
161. the method for claim 160, wherein R is a methyl.
162. the method for claim 160, wherein R is an ethyl.
163. the method for claim 160, the described solvent or the solvent mixture that wherein are used for step (a) comprise toluene, ortho-xylene, meta-xylene, paraxylene or their mixture.
164. the method for claim 163, wherein said solvent or solvent mixture are toluene.
165. the method for claim 160, wherein said tertiary amine base are trialkylamine, tri-alkoxy amine or the heteroaromatic alkali that contains the pyridine residue.
166. the method for claim 165, wherein said tertiary amine base are selected from triethylamine, pyridine, lutidines and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene.
167. the method for claim 166, wherein said tertiary amine base are triethylamine.
168. the method for claim 160, described 2 in the step (a) wherein, 4-dimethoxybenzylamine or its salt are that the form with ammonium salt exists at first.
169. the method for claim 160, wherein step (a) comprising:
A) in the presence of triethylamine and toluene, make 2,4-dimethoxybenzylamine or its ammonium salt and 2-chloro-2-oxo acetic acid ethyl reaction, described step also comprises following step:
I) make 2,4-dimethoxybenzylamine or its ammonium salt, triethylamine and toluene mix, and form mixture;
Ii) cool off described mixture to about 0 ℃, form the mixture of cooling;
Iii) 2-chloro-2-oxo ethyl acetate is added in the mixture of described cooling, the temperature that keeps described mixture simultaneously is about 10 ℃ or be lower than about 10 ℃, forms reaction solution; With
Iv) make described reaction solution be warming to about 20 ℃ to about 27 ℃, form impure 2-(2,4-dimethoxy-benzyl amino)-2-oxo ethyl acetate.
170. the method for claim 160, the solution of wherein said 2-(2,4-dimethoxy-benzylamino)-2-oxo acetic acid esters is also through following one or more step process:
A) aqueous hydrochloric acid solution is added in the solution of described 2-(2,4-dimethoxy-benzyl amino)-2-oxo acetic acid esters, forms water and the organic liquid phase that contains described 2-(2,4-dimethoxy-benzyl amino)-2-oxo acetic acid esters;
B) the described organic liquid phase that contains 2-(2,4-dimethoxy-benzyl amino)-2-oxo acetic acid esters is separated also drying, formed the anhydrous solution of described 2-(2,4-dimethoxy-benzyl amino)-2-oxo acetic acid esters.
171. the method for claim 170, wherein said method comprises following step:
A) from the anhydrous solution of described 2-(2,4-dimethoxy-benzyl amino)-2-oxo acetic acid esters, remove organic solvent, form solid 2-(2,4-dimethoxy-benzyl amino)-2-oxo acetic acid esters; With
B) described solid 2-(2,4-dimethoxy-benzyl-amino)-2-oxo acetic acid esters is carried out purifying.
172. the method for claim 160, wherein step (b) also comprises:
I) 2-(2-amino-ethyl) pyridine is mixed in the solution of step (a), form reaction solution and
Ii) heat described reaction solution, form N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides.
173. the method for claim 172, wherein step (b) also comprises:
I) cool off described reaction solution, form the cooling solution of N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides;
Ii) described N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides is solidified from the solution of described cooling by adding dialkyl ether; With
Iii) collect described solid N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides.
174. the method for claim 173, wherein said method comprises following step:
Described solid N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl]-oxamides of iv) using heptane treatment step (b) to obtain, the slurries of formation N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl]-oxamides; With
V) from described slurries, collect described N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl]-oxamides, obtain purified N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl]-oxamides.
175. method for preparing N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides with following structural formula:
Described method comprises:
A) will have 2 of following structural formula, 4-dimethoxybenzylamine or its ammonium salt are dissolved in triethylamine and the toluene, form mixture:
B) at about 10 ℃ or be lower than about 10 ℃ temperature in the described mixture that step (a) forms, adding 2-chloro-2-oxo ethyl acetate with following structural formula:
Formation has the solution of 2-(2,4-methoxy-benzyl the amino)-2-oxo ethyl acetate of following structural formula:
C) make the solution and 2-(pyridine-2-yl) ethamine reaction of described 2-(2,4-dimethoxy-benzyl the amino)-2-oxo ethyl acetate that forms in step (b) with following structural formula:
Form reaction solution, heat described reaction solution subsequently, form N-(2, the 4-dimethoxy-benzyl)-N '-[2-(pyridine-2-yl) ethyl] oxamides.
176. one kind prepares the 2-H-benzo [3,4-d] 1 with following structural formula, the method for 3-dioxolanes-5-base-N-(propyl group butyl)-formamide:
Described method comprises:
A) make piperonylic acid with following structural formula:
With the reagent reacting that can form acyl chlorides, form piperonyl acyl chlorides with following structural formula:
The described reagent that can form acyl chlorides comprises thionyl chloride, oxalyl chloride, phosphoryl chloride phosphorus oxychloride or their mixture,
B) make piperonyl acyl chlorides that forms in step (a) and 4-heptyl amine reaction with following structural formula:
Form 2-H-benzo [3,4-d] 1,3-dioxolanes-5-base-N-(propyl group butyl)-formamide.
177. the method for claim 176, the wherein said reagent that can form acyl chlorides is thionyl chloride.
178. the method for claim 176, wherein step (a) be selected from following solvent in the presence of carry out: carrene, chloroform, oxolane and their mixture.
179. the method for claim 178, wherein said solvent comprises carrene.
180. the method for claim 178, it also comprises dimethyl formamide.
181. the method for claim 176, wherein step (a) also comprises following step:
I) piperonylic acid, carrene and dimethyl formamide are mixed, form liquid mixture;
Ii) cool off described liquid and be mixed to about 0 ℃, form the mixture of cooling;
Iii), form reactant mixture at about 10 ℃ or be lower than about 10 ℃ temperature and in the mixture of described cooling, add the described reagent that can form acyl chlorides; With
Iv) after adding described acyl chlorides formation reagent, described reactant mixture is heated to backflow, forms the solution of piperonyl acyl chlorides.
182. the method for claim 176, wherein step (a) is carried out in the presence of organic base.
183. the method for claim 182, wherein said organic base are selected from triethylamine, diisopropylethylamine, pyridine, lutidines and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene.
184. the method for claim 183, wherein said organic base are triethylamine.
185. the method for claim 176, wherein step (b) also comprises following step:
I) 4-heptyl amine, triethylamine, carrene and dimethyl formamide are mixed, form the solution of 4-heptyl amine;
Ii) in the solution of described 4-heptyl amine, add described piperonyl acyl chlorides being lower than about 5 ℃ temperature, form reactant mixture; With
Iii) make described reactant mixture be warming to about 20 ℃ to about 25 ℃, form and contain 2-H-benzo [3,4-d] 1, the crude product reaction solution of 3-dioxolanes-5-base-N-(propyl group butyl)-formamide.
186. the method for claim 185, wherein step (b) also comprises:
Iv) make the crude product reaction solution that (iii) obtains in step (b) be cooled to about 0 ℃ to about 5 ℃, and add entry, form two phase liquid;
V) described two phase liquid is handled by the following method: remove water, resulting then organic facies is handled in the following sequence with following solution, forms 2-H-benzo [3,4-d] 1, the solution of 3-dioxolanes-5-base-N-(propyl group butyl)-formamide:
1. being about 0.1N with equivalent handles to the aqueous hydrochloric acid solution of about 2.0N;
2. handle with saturated aqueous solution of sodium bicarbonate; With
3. handle with saturated aqueous sodium chloride;
Vi) remove described organic facies, form crude product 2-H-benzo [3,4-d] 1,3-dioxolanes-5-base-N-(propyl group butyl)-formamide; With
Vii) form described crude product 2-H-benzo [3,4-d] 1, the slurries of 3-dioxolanes-5-base-N-(propyl group butyl)-formamide, isolated by filtration obtains 2-H-benzo [3,4-d] 1 then, 3-dioxolanes-5-base-N-(propyl group butyl)-formamide.
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| CN102311422A (en) * | 2011-07-11 | 2012-01-11 | 上海应用技术学院 | N-(hept-4-yl) benzo [d] [1, 3] dioxole-5-methanamide and synthetic method thereof |
| CN102940224A (en) * | 2011-05-31 | 2013-02-27 | 西姆莱斯有限公司 | Cinnamamides as savory flavorings |
| CN103156154A (en) * | 2011-12-09 | 2013-06-19 | 味之素株式会社 | Sweetening agent composition and drink food |
| CN105962244A (en) * | 2016-06-12 | 2016-09-28 | 安徽徽风生态农业开发有限公司 | Preparation method of bouillon cube long in quality guarantee period and good in taste |
| CN106998771A (en) * | 2014-12-10 | 2017-08-01 | 马斯公司 | Flavour compositions and the pet food comprising said composition |
| WO2020155548A1 (en) * | 2019-01-30 | 2020-08-06 | 上海交通大学 | Bitterness-free low sodium salt with carrageenan added thereto, preparation method therefor and use thereof |
| CN112167560A (en) * | 2020-08-31 | 2021-01-05 | 甘肃雅涛鑫业智慧农业有限责任公司 | Shandan-Huangshen vegetable and preparation method thereof |
| CN114727636A (en) * | 2019-12-18 | 2022-07-08 | 弗门尼舍公司 | Taste-improving composition and use thereof |
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| CN102940224A (en) * | 2011-05-31 | 2013-02-27 | 西姆莱斯有限公司 | Cinnamamides as savory flavorings |
| US9144248B2 (en) | 2011-05-31 | 2015-09-29 | Symrise Ag | Cinnamamides as savory flavorings |
| CN102940224B (en) * | 2011-05-31 | 2016-05-04 | 西姆莱斯有限公司 | Cinnamic acid acid amides is as delicious flavor substance |
| CN102311422A (en) * | 2011-07-11 | 2012-01-11 | 上海应用技术学院 | N-(hept-4-yl) benzo [d] [1, 3] dioxole-5-methanamide and synthetic method thereof |
| CN103156154A (en) * | 2011-12-09 | 2013-06-19 | 味之素株式会社 | Sweetening agent composition and drink food |
| CN106998771A (en) * | 2014-12-10 | 2017-08-01 | 马斯公司 | Flavour compositions and the pet food comprising said composition |
| CN105962244A (en) * | 2016-06-12 | 2016-09-28 | 安徽徽风生态农业开发有限公司 | Preparation method of bouillon cube long in quality guarantee period and good in taste |
| WO2020155548A1 (en) * | 2019-01-30 | 2020-08-06 | 上海交通大学 | Bitterness-free low sodium salt with carrageenan added thereto, preparation method therefor and use thereof |
| CN114727636A (en) * | 2019-12-18 | 2022-07-08 | 弗门尼舍公司 | Taste-improving composition and use thereof |
| CN112167560A (en) * | 2020-08-31 | 2021-01-05 | 甘肃雅涛鑫业智慧农业有限责任公司 | Shandan-Huangshen vegetable and preparation method thereof |
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