CN118459454A - Preparation method of sweet taste regulator - Google Patents
Preparation method of sweet taste regulator Download PDFInfo
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- CN118459454A CN118459454A CN202410920278.4A CN202410920278A CN118459454A CN 118459454 A CN118459454 A CN 118459454A CN 202410920278 A CN202410920278 A CN 202410920278A CN 118459454 A CN118459454 A CN 118459454A
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- 235000019605 sweet taste sensations Nutrition 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 56
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 19
- 238000007112 amidation reaction Methods 0.000 claims abstract description 16
- JRJLLMLYUFAZOM-UHFFFAOYSA-N 2,6-dimethylpyridine-4-carboxylic acid Chemical compound CC1=CC(C(O)=O)=CC(C)=N1 JRJLLMLYUFAZOM-UHFFFAOYSA-N 0.000 claims abstract description 14
- IQUNZGOZUJITBJ-UHFFFAOYSA-N 2-amino-6-fluorobenzonitrile Chemical compound NC1=CC=CC(F)=C1C#N IQUNZGOZUJITBJ-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229940058020 2-amino-2-methyl-1-propanol Drugs 0.000 claims abstract description 13
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 claims abstract description 13
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 9
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 70
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 17
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- 230000035484 reaction time Effects 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 13
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical group [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 239000003607 modifier Substances 0.000 claims description 4
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 239000003054 catalyst Substances 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000007795 chemical reaction product Substances 0.000 abstract description 4
- 235000013305 food Nutrition 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 229910000510 noble metal Inorganic materials 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- 235000013599 spices Nutrition 0.000 abstract description 2
- 238000013341 scale-up Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- -1 [1,2,6] thiadiazin-5-yl Chemical group 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000012043 crude product Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- ZYDGHQSJZAFMLU-UHFFFAOYSA-N 2,6-dinitrobenzonitrile Chemical compound [O-][N+](=O)C1=CC=CC([N+]([O-])=O)=C1C#N ZYDGHQSJZAFMLU-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- TWYFAQINESPVDB-UHFFFAOYSA-N n-[1-[(4-amino-2,2-dioxo-1h-2$l^{6},1,3-benzothiadiazin-5-yl)oxy]-2-methylpropan-2-yl]-2,6-dimethylpyridine-4-carboxamide Chemical compound CC1=NC(C)=CC(C(=O)NC(C)(C)COC=2C=3C(N)=NS(=O)(=O)NC=3C=CC=2)=C1 TWYFAQINESPVDB-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 235000013615 non-nutritive sweetener Nutrition 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 231100000041 toxicology testing Toxicity 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 235000019577 caloric intake Nutrition 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000007673 developmental toxicity Effects 0.000 description 1
- 231100000415 developmental toxicity Toxicity 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 231100000138 genotoxicity study Toxicity 0.000 description 1
- 108091005708 gustatory receptors Proteins 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229940126027 positive allosteric modulator Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of a sweet taste regulator, and belongs to the technical field of food spice synthesis. The preparation method provided by the invention takes 2, 6-dimethyl-4-picolinic acid as a starting material, and the starting material is subjected to amidation reaction with 2-amino-2-methyl-1-propanol, then the amidation reaction product is subjected to aromatic nucleophilic substitution reaction with 2-amino-6-fluorobenzonitrile after being reacted with strong alkali, then the aromatic nucleophilic substitution reaction product is subjected to nucleophilic substitution reaction with sulfamoyl chloride, and finally the nucleophilic substitution reaction product is subjected to intramolecular cyclization reaction under alkaline conditions, so that the sweet taste regulator is obtained. The method provided by the invention has the advantages of short steps, simple operation, cheap and easily available raw materials, no need of noble metal catalysts, safe and efficient reaction and the like, and is suitable for industrial scale-up production.
Description
Technical Field
The invention relates to the technical field of food spice synthesis, in particular to a preparation method of a sweet taste regulator.
Background
The information disclosed in the background of the invention is only for enhancement of understanding of the general background of the invention and is not necessarily to be taken as an admission or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art.
The mass intake of sugar by people causes more and more people with obesity, and obesity usually causes metabolic disorder of human body, so that the tolerance of the human body to sugar is reduced, which is one of important factors for inducing type 2 diabetes. Non-caloric sweeteners reduce sugar intake while improving the flavor of foods and beverages, and therefore the synthesis and use of such non-caloric sweeteners is of great interest.
N- (1- ((4-amino-2, 2-dioxo-1H-benzo [ c ] [1,2,6] thiadiazin-5-yl) oxy) -2-methylpropan-2-yl) -2, 6-dimethylisonicotinamide is a positive allosteric modulator of the human sweet taste receptor, which can reduce caloric intake while maintaining the flavor of natural sugar, and has the structural formula shown as follows:
。
The sweet taste modulator was originally filed by the company of celecox in the united states in 2014 for patent application (US 20140235624 A1) and studied in the international journal of the core "toxicology study" in 2017 (Toxicology Reports,2017, volume 4, pages 507-520) for toxicity as a food flavor application from aspects of in vitro/in vivo metabolism and in vivo pharmacokinetic studies, general toxicology studies in rodents, genotoxicity studies and developmental toxicity studies.
Patent application US20140235624A1 synthesizes N- (1- ((4-amino-2, 2-dioxy-1H-benzo [ c ] [1,2,6] thiadiazin-5-yl) oxy) -2-methylpropan-2-yl) -2, 6-dimethylisonicotinamide sweetener by six steps of reaction using 2, 6-dinitrobenzonitrile as raw material: ① Under alkaline condition, 2-amino-2-methyl-1-propanol and 2, 6-dinitrobenzonitrile undergo nucleophilic substitution reaction to generate an ether intermediate, and the ether intermediate is protected by tert-butoxycarbonyl (Boc) to obtain a compound IX; ② Reducing compound IX to compound VIII under 40 psi hydrogen conditions with Pd/C as a catalyst; ③ Under alkaline conditions, reacting the compound VIII with sulfamoyl chloride to generate a compound VII; ④ In NaOH ethanol solution, carrying out cyclization reaction on the compound VII at high temperature to generate a compound VI; ⑤ Hydrolyzing the compound VI under an acidic condition to obtain hydrochloride V; ⑥ Under alkaline conditions, 2, 6-dimethyl-4-picolinic acid is activated by an amide condensing agent and reacts with the compound V to generate the compound I. The reaction route is shown in the following formula:
。
the synthesis steps of the reaction route are complex and tedious, six steps of reactions are carried out altogether, the protection and deprotection of functional groups are involved, the 2, 6-dinitrobenzonitrile serving as a reaction raw material is not safe and is difficult to purchase, the Pd/C catalyst with high price is adopted in the reaction, the cost is greatly increased, and the reduction of Pd/C hydrogen is carried out under the condition of high pressure, so that certain potential safety hazard exists, and the industrial production is not facilitated.
Therefore, it would be a great need to provide a process for preparing N- (1- ((4-amino-2, 2-dioxo-1H-benzo [ c ] [1,2,6] thiadiazin-5-yl) oxy) -2-methylpropan-2-yl) -2, 6-dimethylisonicotinamide sweetness modifier that is inexpensive and easily available as starting material, simple in operation steps and does not require a noble metal catalyst.
Disclosure of Invention
In view of the above, the invention provides a preparation method of a sweet taste regulator, which solves the problems of complicated steps, low safety of initial raw materials, few sources, expensive catalysts and high preparation cost of the existing preparation method of N- (1- ((4-amino-2, 2-dioxy-1H-benzo [ c ] [1,2,6] thiadiazine-5-yl) oxy) -2-methylpropan-2-yl) -2, 6-dimethyl isonicotinamide.
The invention provides a preparation method of a sweet taste regulator, which comprises the following steps:
Step 1, carrying out amidation reaction on 2, 6-dimethyl-4-picolinic acid and 2-amino-2-methyl-1-propanol to obtain a compound shown in a formula (I);
Step 2, reacting a compound shown in a formula (I) with strong alkali, and then carrying out aromatic nucleophilic substitution reaction with 2-amino-6-fluorobenzonitrile to obtain a compound shown in a formula (II);
step 3, nucleophilic substitution reaction is carried out on the compound shown in the formula (II) and sulfamoyl chloride, so as to obtain a compound shown in the formula (III);
Step 4, carrying out intramolecular cyclization reaction on a compound shown in a formula (III) under an alkaline condition to obtain the sweet taste regulator, wherein the structural formula of the sweet taste regulator is shown in a formula (IV);
Formula (I); Formula (II); Formula (III); formula (IV).
Preferably, the solvent for the amidation reaction in the step 1 is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methylene dichloride or dimethyl sulfoxide, and the condensing agent for the amidation reaction is N, N '-dicyclohexylcarbodiimide or N, N' -carbonyldiimidazole; the molar ratio of the condensing agent to the 2, 6-dimethyl-4-picolinic acid is (0.95-1.05): 1.
Preferably, the reaction temperature of the amidation reaction in the step 1 is 15-30 ℃ and the reaction time is 10-15 h.
Preferably, in the step 1, the molar ratio of the 2, 6-dimethyl-4-picolinic acid to the 2-amino-2-methyl-1-propanol is 1 (1-1.1).
Preferably, the solvent for the reaction of the compound of formula (I) in step 2 with a strong base is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether or toluene; the strong base is selected from sodium hydride or potassium tert-butoxide; the reaction temperature of the compound shown in the formula (I) and the strong alkali is-5 ℃, and the reaction time is 0.5-2 h; the temperature of the nucleophilic substitution reaction of the aromatic hydrocarbon with the 2-amino-6-fluorobenzonitrile is 80-90 ℃, and the reaction time is 10-20 h.
Preferably, the molar ratio of the compound shown in the formula (I), the strong base and the 2-amino-6-fluorobenzonitrile in the step (2) is 1 (1.05-1.2) to 1.05-1.2.
Preferably, the solvent for nucleophilic substitution reaction in the step 3 is N, N-dimethylformamide or N, N-dimethylacetamide, the reaction temperature is 0-30 ℃, and the reaction time is 2-8 hours.
Preferably, the molar ratio of the compound shown in the formula (II) in the step 3 to the sulfamoyl chloride is1 (1.5-3.5).
Preferably, the solvent for the intramolecular cyclization reaction in the step4 is an ethanol aqueous solution of sodium hydroxide, the reaction temperature is 60-80 ℃, and the reaction time is 10-20 hours.
Further, the molar ratio of the compound shown in the formula (III) to sodium hydroxide is 1 (3-4); the volume ratio of ethanol to water in the ethanol water solution is 1 (0.5-1).
Compared with the prior art, the invention has the following beneficial effects:
The invention provides a new synthetic route for synthesizing a sweet taste regulator N- (1- ((4-amino-2, 2-dioxy-1H-benzo [ c ] [1,2,6] thiadiazine-5-yl) oxy) -2-methylpropane-2-yl) -2, 6-dimethyl isonicotinamide, and the method provided by the invention has the synthetic advantages of shorter steps, simplicity in operation, cheap and easily available raw materials, no need of noble metal catalysts, safe and efficient reaction and the like, and is suitable for industrialized amplification production.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention. It will be obvious to those skilled in the art that other figures may be obtained from these figures without the inventive effort.
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound represented by the formula (II) of example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of a compound represented by the formula (IV) of example 1 of the present invention;
FIG. 3 is a high performance liquid chromatography of the compound of formula (IV) according to example 1 of the present invention.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The invention provides a preparation method of a sweet taste regulator, which comprises the following steps:
Step 1, carrying out amidation reaction on 2, 6-dimethyl-4-picolinic acid and 2-amino-2-methyl-1-propanol to obtain a compound shown in a formula (I);
Step 2, reacting a compound shown in a formula (I) with strong alkali, and then carrying out aromatic nucleophilic substitution reaction with 2-amino-6-fluorobenzonitrile to obtain a compound shown in a formula (II);
step 3, nucleophilic substitution reaction is carried out on the compound shown in the formula (II) and sulfamoyl chloride, so as to obtain a compound shown in the formula (III);
Step 4, carrying out intramolecular cyclization reaction on a compound shown in a formula (III) under an alkaline condition to obtain the sweet taste regulator, wherein the structural formula of the sweet taste regulator is shown in a formula (IV);
Formula (I); Formula (II); Formula (III); formula (IV).
The invention obtains the sweet taste regulator shown in the formula (IV) through four steps of reactions, namely N- (1- ((4-amino-2, 2-dioxy-1H-benzo [ c ] [1,2,6] thiadiazin-5-yl) oxy) -2-methylpropan-2-yl) -2, 6-dimethyl isonicotinamide. The invention takes 2, 6-dimethyl-4-picolinic acid as the initial raw material, and has wider sources, lower price and higher safety compared with the 2, 6-dinitrobenzonitrile in the prior art.
The solvent for the amidation reaction in step 1 of the present invention is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methylene chloride or dimethyl sulfoxide, and the condensing agent for the amidation reaction is N, N ' -Dicyclohexylcarbodiimide (DCC) or N, N ' -Carbonyldiimidazole (CDI), more preferably N, N ' -dicyclohexylcarbodiimide. The amount of the solvent used in the present invention is not particularly limited, and may be any amount as long as it is a solvent used in the conventional amidation reaction by those skilled in the art.
In the invention, the amidation reaction in the step 1 has a reaction temperature of 15-30 ℃ and a reaction time of 10-15 h, and the molar ratio of 2, 6-dimethyl-4-picolinic acid to 2-amino-2-methyl-1-propanol is 1 (1-1.1), more preferably 1 (1-1.05). In the invention, in order to ensure that the reaction is performed smoothly, 2-amino-2-methyl-1-propanol is firstly dissolved in a solvent in a feeding stage and then is dropwise added into a solution containing 2, 6-dimethyl-4-picolinic acid under the condition of ice water bath. The present invention further comprises a post-treatment step after the completion of the amidation reaction, and the present invention is not particularly limited to the post-treatment step, and a person skilled in the art can obtain an amidated product having a higher purity according to conventional post-treatment means in the art.
The solvent for the reaction of the compound shown in the formula (I) in the step 2 is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tertiary butyl ether or toluene. The strong base is selected from sodium hydride or potassium tert-butoxide, and the sodium hydride and the potassium tert-butoxide can react with the compound shown in the formula (I) to generate sodium alkoxide or potassium alkoxide and release hydrogen. In order to avoid excessively severe reaction, the temperature of the reaction of the compound shown in the formula (I) and strong base is-5 ℃, the reaction time is 0.5-2 h, and the strong base is added in multiple batches. After sodium alkoxide or potassium alkoxide is generated, 2-amino-6-fluorobenzonitrile is directly added into the solution to carry out aromatic nucleophilic substitution reaction, the reaction temperature is 80-90 ℃, and the reaction time is 10-20 hours. The molar ratio of the compound shown in the formula (I) in the step 2 to the strong base to the 2-amino-6-fluorobenzonitrile is 1 (1.05-1.2): 1.05-1.2, more preferably 1 (1.10-1.15): 1.10-1.15, and most preferably 1:1.11:1.11.
The solvent for nucleophilic substitution reaction in step 3 of the present invention is N, N-Dimethylformamide (DMF) or N, N-Dimethylacetamide (DMA). The reaction temperature of the nucleophilic substitution reaction is 0-30 ℃, and the reaction time is 2-8 hours. The nucleophilic substitution reaction in step 3 may be performed in a stepwise temperature rising manner. The molar ratio of the compound shown in the formula (II) in the step 3 to the sulfamoyl chloride is 1 (1.5-3.5), more preferably 1 (2-3), and the sulfamoyl chloride is preferably added in multiple batches.
In the step 4, the solvent for the intramolecular cyclization reaction is an ethanol water solution of sodium hydroxide, and the reaction temperature is 60-80 ℃, preferably 62-70 ℃, more preferably 63-67 ℃; the reaction time is 8-15 h. In the present invention, the molar ratio of the compound represented by the formula (III) to sodium hydroxide is 1 (3 to 4), more preferably 1 (3 to 3.5). The volume ratio of ethanol to water in the ethanol aqueous solution is preferably 1 (0.5-1).
The technical scheme of the invention is further described below by combining specific embodiments. The reagents in the examples below were all commercially available. The amounts of reactants in each step of the examples do not affect the use of other steps and if the amount of reaction product does not meet the use of other steps, it may be prepared multiple times to meet the amount required for other steps.
In the examples below, DCC represents N, N '-dicyclohexylcarbodiimide, PE represents petroleum ether, EA represents ethyl acetate, DMA represents N, N-dimethylacetamide, CDI represents N, N' -carbonyldiimidazole, DMF represents N, N-dimethylformamide, CDCl 3 represents deuterated chloroform, DMSO-d 6 represents deuterated dimethyl sulfoxide.
Example 1
This example provides a process for the preparation of the sweetness modifier N- (1- ((4-amino-2, 2-dioxo-1H-benzo [ c ] [1,2,6] thiadiazin-5-yl) oxy) -2-methylpropan-2-yl) -2, 6-dimethylisonicotinamide, the reaction scheme is shown below:
。
(1) Synthesis of compounds of formula (I):
To a 1L clean three-necked flask equipped with a stirrer and a thermometer, 20g of 2, 6-dimethyl-4-pyridinecarboxylic acid (0.132 mol) was added, 200g of tetrahydrofuran was added, stirring was turned on under the protection of nitrogen, and a solution of DCC (0.136 mol) in tetrahydrofuran (28 g of DCC, 200g of tetrahydrofuran) was slowly added dropwise, and the reaction was continued for 1 hour after the completion of the dropwise addition. The reaction system was cooled to 0℃and a tetrahydrofuran solution (12 g of 2-amino-2-methyl-1-propanol, 200g of tetrahydrofuran) of 2-amino-2-methyl-1-propanol (0.135 mol) was slowly added dropwise thereto, and after completion of the dropwise addition, the reaction was continued for 1 hour and then allowed to proceed to room temperature for 12 hours. After the reaction was completed, impurities were removed by filtration, and the mother liquor was concentrated to obtain a crude product, which was recrystallized from PE and EA to obtain 25g of a compound (0.112 mol) represented by the formula (I) in 85% yield.
(2) Synthesis of compounds of formula (II):
150g of 2-methyltetrahydrofuran and 22g of the compound of formula (I) (0.099 mol) were placed in a 500mL clean three-necked flask equipped with a stirrer, a thermometer and a condenser, stirring was started under nitrogen at 0℃and 4.4g of sodium hydride (wherein the sodium hydride content was 60%,0.11 mol) was gradually added in portions, the reaction was continued for 1 hour after the completion of the addition, and a 2-methyltetrahydrofuran solution of 2-amino-6-fluorobenzonitrile (0.11 mol) (15 g of 2-amino-6-fluorobenzonitrile, 100g of 2-methyltetrahydrofuran) was added dropwise to the system. After the dripping is finished, the reaction is carried out for 1 hour at a temperature of 87 ℃ and then is carried out for 15 hours. After the reaction, the mixture was quenched with saturated aqueous ammonium chloride, extracted 3 times with 400mL of methylene chloride, the organic phases were combined, desolventized under reduced pressure to give a crude product, which was recrystallized from petroleum ether and methyl tert-butyl ether to give 24g of the compound (0.071 mol) of the formula (II) in a yield of 72%. The nuclear magnetic resonance hydrogen spectrum of the compound shown in the formula (II) is shown in figure 1. Analysis of nuclear magnetic resonance hydrogen spectrum ：1H NMR (400 MHz, CDCl3), δ = 7.44 (s, 1H), 7.20 (s, 2H), 7.13 (t,J= 8.4 Hz, 1H), 6.24 (d,J= 8.4 Hz, 1H), 6.21 – 6.15 (m, 2H), 4.35 (s, 2H), 4.14 (s, 2H), 2.52 (s, 1H), 2.50 (s, 6H), 1.53 (s, 6H).
(3) Synthesis of compounds of formula (III):
50mL of anhydrous DMA and 24g of the compound (0.071 mol) shown in the formula (II) were added into a 250mL clean three-necked flask equipped with a stirrer and a thermometer under the nitrogen condition at 0 ℃, a DMA solution (21 g of sulfamoyl chloride, 40g of DMA) of sulfamoyl chloride (0.182 mol) was added dropwise into the reaction system in batches, the reaction was continued for 1 hour after the addition was completed, the reaction was transferred to room temperature for 4 hours, the reaction solution was poured into 200mL of cold water after the reaction was completed, a white solid was generated, 28g of the compound (0.067 mol) shown in the formula (III) was obtained by filtration and collection, and the yield was 94%.
(4) Synthesis of compounds of formula (IV):
To a 500mL clean three-necked flask equipped with a stirrer, a thermometer and a condenser were added 173mL of ethanol and 28g of the compound represented by the formula (III) (0.067 mol), and 110mL of an aqueous solution of sodium hydroxide (0.22 mol) having a concentration of 2M was slowly added to the system, and the temperature was raised to 65℃for reaction for 15 hours. After the reaction, ethanol was removed by rotary evaporation, the reaction mixture was diluted with 180mL of water, the pH of the system was adjusted to 6 with 1M hydrochloric acid, the solid crude product was collected by filtration, ethanol was added to the crude product, heated to reflux, cooled to 0 ℃ after 1h, the solid was collected by filtration and dried under vacuum to give 22g of the final product of the compound of formula (IV) (0.053 mol) in 79% yield. The nuclear magnetic resonance hydrogen spectrum of the compound shown in the formula (IV) is shown in figure 2; the purity of the compound represented by the formula (IV) was 99.56% as measured by high performance liquid chromatography as shown in fig. 3. Analysis of nuclear magnetic resonance hydrogen spectrum ：1H NMR (400 MHz, DMSO-d6), δ = 11.03 (s, 1H), 8.50 (s, 1H), 8.37 (s, 1H), 7.84 (d,J= 3.6 Hz, 1H), 7.47 (t,J= 8.4 Hz, 1H), 7.30 (s, 2H), 6.78 (d,J= 8.4 Hz, 1H), 6.64 (d,J= 8.4 Hz, 1H), 4.38 (s, 2H), 2.46 (s, 6H), 1.47 (s, 6H).
Example 2
This example provides a method for preparing a sweetness modifier N- (1- ((4-amino-2, 2-dioxo-1H-benzo [ c ] [1,2,6] thiadiazin-5-yl) oxy) -2-methylpropan-2-yl) -2, 6-dimethylisonicotinamide.
(1) Synthesis of compounds of formula (I):
To a 1L clean three-necked flask equipped with a stirrer and a thermometer, 20g of 2, 6-dimethyl-4-pyridinecarboxylic acid (0.132 mol) was added, 200g of tetrahydrofuran was added, and under the protection of nitrogen gas, stirring was started to slowly drop a solution of CDI (0.130 mol) in tetrahydrofuran (CDI 21g, 200g of tetrahydrofuran), and the reaction was continued for 1 hour after the completion of the drop. The reaction system was cooled to 0℃and a tetrahydrofuran solution (12 g of 2-amino-2-methyl-1-propanol, 200g of tetrahydrofuran) of 2-amino-2-methyl-1-propanol (0.135 mol) was slowly added dropwise thereto, and after completion of the dropwise addition, the reaction was continued for 1 hour and then allowed to proceed to room temperature for 12 hours. After the reaction, impurities were removed by filtration, and the mother liquor was concentrated to give a crude product, which was recrystallized from PE and EA to give 17g of a compound (0.077 mol) represented by the formula (I) in 58% yield.
(2) Synthesis of compounds of formula (II):
150g of 2-methyltetrahydrofuran and 22g of the compound of formula (I) (0.099 mol) were placed in a 500mL clean three-necked flask equipped with a stirrer, a thermometer and a condenser, stirring was started under nitrogen at 0℃and 12.3g of potassium t-butoxide (0.11 mol) was gradually added in portions, and after completion of the addition, the reaction was continued for 1 hour, and a 2-methyltetrahydrofuran solution of 2-amino-6-fluorobenzonitrile (0.11 mol) (15 g of 2-amino-6-fluorobenzonitrile, 100g of 2-methyltetrahydrofuran) was added dropwise to the system. After the dripping is finished, the reaction is carried out for 1 hour at a temperature of 87 ℃ and then is carried out for 15 hours. After the reaction, the mixture was quenched with saturated aqueous ammonium chloride, extracted 3 times with 400mL of methylene chloride, the organic phases were combined, desolventized under reduced pressure to give a crude product, which was recrystallized from petroleum ether and methyl tert-butyl ether to give 23g of the compound of formula (II) (0.068 mol) in 69% yield.
(3) Synthesis of compounds of formula (III):
50mL of anhydrous DMF and 24g of the compound (0.071 mol) represented by the formula (II) were added to a 250mL of a clean three-necked flask equipped with a stirrer and a thermometer under nitrogen condition at 0 ℃, a DMF solution (21 g of sulfamoyl chloride, 40g of DMF) of sulfamoyl chloride (0.182 mol) was added dropwise to the reaction system in batches, the reaction was continued for 1 hour after the addition was completed, the reaction was allowed to proceed to room temperature for 4 hours, the reaction solution was poured into 200mL of cold water after the reaction was completed, a white solid was formed, and 26g of the compound (0.062 mol) represented by the formula (III) was obtained by filtration and collected as a white solid, the yield was 87%.
(4) Synthesis of compounds of formula (IV):
173mL of ethanol and 28g of the compound represented by formula (III) (0.067 mol) were charged into a 500mL clean three-necked flask equipped with a stirrer, a thermometer and a condenser, 110mL of a 2M aqueous sodium hydroxide solution (0.22 mol) was slowly added to the system, and the temperature was raised to 100℃for reaction for 15 hours. After the reaction, ethanol was removed by rotary evaporation, the reaction mixture was diluted with 180mL of water, the pH of the system was adjusted to 6 with 1M hydrochloric acid, the solid crude product was collected by filtration, ethanol was added to the crude product, heated to reflux, cooled to 0 ℃ after 1h, the solid was collected by filtration and dried under vacuum to give 21g of the compound of formula (IV) (0.051 mol), yield 76% and purity 99%.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for preparing a sweet taste modifier, comprising the steps of:
Step 1, carrying out amidation reaction on 2, 6-dimethyl-4-picolinic acid and 2-amino-2-methyl-1-propanol to obtain a compound shown in a formula (I);
Step 2, reacting a compound shown in a formula (I) with strong alkali, and then carrying out aromatic nucleophilic substitution reaction with 2-amino-6-fluorobenzonitrile to obtain a compound shown in a formula (II);
step 3, nucleophilic substitution reaction is carried out on the compound shown in the formula (II) and sulfamoyl chloride, so as to obtain a compound shown in the formula (III);
Step 4, carrying out intramolecular cyclization reaction on a compound shown in a formula (III) under an alkaline condition to obtain the sweet taste regulator, wherein the structural formula of the sweet taste regulator is shown in a formula (IV);
Formula (I); Formula (II); Formula (III); formula (IV).
2. The preparation method according to claim 1, wherein the solvent for the amidation reaction in step 1 is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methylene chloride or dimethyl sulfoxide, and the condensing agent for the amidation reaction is N, N '-dicyclohexylcarbodiimide or N, N' -carbonyldiimidazole; the molar ratio of the condensing agent to the 2, 6-dimethyl-4-picolinic acid is (0.95-1.05): 1.
3. The preparation method according to claim 1, wherein the amidation reaction in step 1 has a reaction temperature of 15 to 30 ℃ and a reaction time of 10 to 15 hours.
4. The method according to claim 1, wherein in the step 1, the molar ratio of 2, 6-dimethyl-4-picolinic acid to 2-amino-2-methyl-1-propanol is 1 (1 to 1.1).
5. The preparation method according to claim 1, wherein the solvent for the reaction of the compound of formula (I) with a strong base in step 2 is one or more selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl t-butyl ether and toluene; the strong base is selected from sodium hydride or potassium tert-butoxide; the reaction temperature of the compound shown in the formula (I) and the strong alkali is-5 ℃, and the reaction time is 0.5-2 h; the temperature of the nucleophilic substitution reaction of the aromatic hydrocarbon with the 2-amino-6-fluorobenzonitrile is 80-90 ℃, and the reaction time is 10-20 h.
6. The method of claim 1, wherein the molar ratio of the compound of formula (I), the strong base and the 2-amino-6-fluorobenzonitrile in step 2 is 1 (1.05-1.2): 1.05-1.2.
7. The method according to claim 1, wherein the solvent for nucleophilic substitution reaction in step 3 is N, N-dimethylformamide or N, N-dimethylacetamide, the reaction temperature is 0 to 30 ℃, and the reaction time is 2 to 8 hours.
8. The process according to claim 1, wherein the molar ratio of the compound of formula (II) to sulfamoyl chloride in step 3 is 1 (1.5-3.5).
9. The preparation method of claim 1, wherein the solvent for the intramolecular cyclization reaction in step 4 is an aqueous ethanol solution of sodium hydroxide, the reaction temperature is 60-80 ℃, and the reaction time is 10-20 hours.
10. The preparation method according to claim 9, wherein the molar ratio of the compound represented by formula (III) to sodium hydroxide is 1 (3-4); the volume ratio of ethanol to water in the ethanol water solution is 1 (0.5-1).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201440667A (en) * | 2013-02-19 | 2014-11-01 | Senomyx Inc | Sweet flavor modifier |
| US20170354175A1 (en) * | 2017-05-15 | 2017-12-14 | Senomyx, Inc. | Sweetener composition |
| CN113402411A (en) * | 2021-03-15 | 2021-09-17 | 深圳市谦陌通辰实验有限公司 | Oxidation reaction-based synthesis method of propyzamide |
| CN115340513A (en) * | 2022-09-26 | 2022-11-15 | 济南悟通生物科技有限公司 | Preparation method of 2-methyl-3-methylmercaptofuran |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201440667A (en) * | 2013-02-19 | 2014-11-01 | Senomyx Inc | Sweet flavor modifier |
| US20170354175A1 (en) * | 2017-05-15 | 2017-12-14 | Senomyx, Inc. | Sweetener composition |
| CN113402411A (en) * | 2021-03-15 | 2021-09-17 | 深圳市谦陌通辰实验有限公司 | Oxidation reaction-based synthesis method of propyzamide |
| CN115340513A (en) * | 2022-09-26 | 2022-11-15 | 济南悟通生物科技有限公司 | Preparation method of 2-methyl-3-methylmercaptofuran |
Non-Patent Citations (1)
| Title |
|---|
| PIERRE DUCRAY ET AL.: "Discovery of amino-acetonitrile derivatives, a new class of synthetic anthelmintic compounds", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, 29 March 2008 (2008-03-29), pages 2935 - 2938, XP022634984, DOI: 10.1016/j.bmcl.2008.03.071 * |
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