CN112624977A - Anserine intermediate, preparation method of anserine and anserine intermediate - Google Patents
Anserine intermediate, preparation method of anserine and anserine intermediate Download PDFInfo
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Abstract
The invention provides a anserine intermediate shown in a formula (II) and a preparation method thereof, and the preparation method comprises the following steps: the method has the advantages of simple and easy operation, stable process, easy control, convenient treatment after reaction, good product yield and high quality, can be economically and conveniently used for industrial production, and has the following reaction route:
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to an anserine intermediate and a preparation method thereof.
Background
Anserine is an important natural histidine dipeptide and is widely found in muscle and brain tissues of vertebrates. Anserine has a pKa of 7.04 and is therefore a highly efficient natural physiological buffer. Anserine has obvious functions of reducing uric acid, resisting oxidation, resisting aging and the like, and is widely applied to the food industry. The muscle of deep sea fish or livestock and poultry contains a certain amount of anserine, but the content is often low, the extraction process is complicated and the purity of the extract is low. In recent years, with the increasing demand of anserine in the fields of food and medicine, the development of an industrial preparation method of anserine to replace the traditional extraction process is more and more urgent.
In 1964, the preparation method of anserine is reported for the first time by Rinderknecht and the like: n (tau) -methyl-L-histidine benzyl ester and alanine protected by phthaloyl are subjected to hydrazinolysis after condensation, and form salt with nitric acid to obtain anserine nitrate, and the anserine is obtained after the exchange of the nitrate and ion exchange resin, wherein the reaction route is as follows:
the yield of the condensation step of the route is only 65 percent, and the operation is complicated; during phthaloyl removal, highly toxic and explosive hydrazine is used, anserine obtained after deprotection cannot be directly separated from a system, nitrate needs to be taken out firstly, and then free alkali of the anserine can be taken out after ion resin exchange, so that commercial production is not facilitated.
In 2005, the following route was disclosed in JP2005082571A by hamamelis chemical industry: after methyl esterification of the carnosine protected by phthaloyl, selective benzoylation of imidazole, methylation, and finally removal of phthaloyl to obtain whale carnosine, the reaction route is as follows:
the reaction of the benzoylation step is complicated and the yield is low when the route is reproduced in a laboratory, and the feasibility of industrial production is not realized.
In 2007, PaulWatts et al reported the following routes on Synthesis 2007,17, 2608-:
the laboratory repeats the ethanol extraction desalination reported in this document to yield product residues in excess of 30%. Meanwhile, column chromatography is used for many times in the synthesis, so that the application of the method in industrial production is limited.
Therefore, a synthetic route for preparing anserine, which has cheap and easily available raw materials and auxiliary materials, is simple and convenient to operate and is suitable for industrial production, is urgently needed to be provided.
Disclosure of Invention
An object of the present invention is to provide an anserine intermediate compound (II) having the following formula:
the invention also aims to provide a preparation method of the compound (II), which has the advantages of simple and convenient operation, mild reaction conditions and high yield and is suitable for industrial production.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
a preparation method of anserine intermediate shown in formula (II) comprises the following steps of condensing compound (III) with compound (IV) in a solvent in the presence or absence of alkali to obtain compound (II):
in a further improvement, the method comprises the steps of forming a mixed anhydride by the compound (III) and a chloroformate compound or pivaloyl chloride, and condensing the mixed anhydride and the compound (IV) to obtain the compound (II), wherein the chloroformate compound comprises one or more of isobutyric acid chloroformate, ethyl chloroformate, methyl chloroformate or isopropyl chloroformate.
In a further improvement, the process comprises condensing compound (III) with compound (IV) in the presence of a condensing agent to provide compound (II), the amine compound comprising one or more of carbonyldiimidazole, dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
In a further improvement, the base is one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, trimethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene, or 1, 4-diazabicyclo [2.2.2] octane, preferably one or more of carbocyclylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, 4-diazabicyclo [2.2.2] octane; preferably one or more of carbocyclylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, 4-diazabicyclo [2.2.2] octane; the solvent is selected from benzene, toluene, chlorobenzene, xylene, isopropylbenzene, acetonitrile, benzonitrile, ethyl acetate, isopropyl acetate, 2-butanone, acetone, 1, 2-dimethyl-2-imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl ammonium phosphate, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, pyridine, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, t-butanol, t-amyl alcohol, polyethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1, 2-propylene glycol, diethoxymethane, dioxane, methyl t-butyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-hexane, cyclohexane, dichloromethane, toluene, ethyl acetate, isopropyl alcohol, ethylene glycol, t-butyl alcohol, t-amyl alcohol, One or more of 1, 2-dichloroethane, or chloroform; preferably one or more of toluene, dichloromethane, acetonitrile, ethylene glycol dimethyl ether, diethoxymethane, dioxane, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, tetrahydrofuran or 2-methyltetrahydrofuran.
In a further improvement, the feeding molar ratio of the compound (IV) to the compound (III) is 0.6-3: 1; preferably 0.8-2: 1; the feeding molar ratio of the chloroformate or pivaloyl chloride to the compound (IV) is 0.6-1.5:1, preferably 0.9-1.2: 1; the feeding molar ratio of the condensing agent to the compound (IV) is 0.6-5:1, preferably 0.9-1.5: 1; when the compound (III) is a free base, the feeding molar ratio of the base to the compound (III) is 0.6-5:1, preferably 0.8-2: 1; when compound (III) is the hydrochloride salt, the molar ratio of the base to compound (III) charged is from 2.6 to 7:1, preferably from 2.8 to 4: 1; the reaction temperature is-78-150 ℃, and preferably-10-130 ℃; the reaction time is 0.5 to 36 hours, preferably 1 to 24 hours.
The invention also aims to provide a method for preparing anserine (I) from the compound (II), which has the advantages of simple operation, stable quality, good selectivity, high yield and suitability for industrial production.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
in the presence of a catalyst, reacting a compound (II) in a solvent in a reducing agent to obtain a compound (I), namely anserine, wherein the reaction equation is as follows:
in a further improvement, the catalyst is one or more of palladium carbon, palladium black, palladium hydroxide/carbon or Raney nickel; the reducing agent is one or more of hydrogen, ammonium formate, formic acid/triethylamine, ethanol, methanol or isopropanol; the solvent is selected from benzene, toluene, chlorobenzene, xylene, isopropylbenzene, acetonitrile, benzonitrile, ethyl acetate, isopropyl acetate, 2-butanone, acetone, 1, 2-dimethyl-2-imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl ammonium phosphate, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, pyridine, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, t-butanol, t-amyl alcohol, polyethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1, 2-propylene glycol, diethoxymethane, dioxane, methyl t-butyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-hexane, cyclohexane, dichloromethane, toluene, ethyl acetate, isopropyl alcohol, ethylene glycol, t-butyl alcohol, t-amyl alcohol, One or more of 1, 2-dichloroethane, chloroform, or water; preferably one or more of methanol, ethanol, tetrahydrofuran, ethyl acetate or water.
The further improvement is that when the catalyst is one or more of palladium carbon, palladium black, palladium hydroxide and palladium hydroxide/carbon, the mass ratio of the Pd content in the catalyst to the feeding amount of the compound (II) is 0.001-0.5:1, preferably 0.005-0.2: 1; when the catalyst is Raney nickel, the mass ratio of the catalyst to the compound (II) is 0.001-0.5:1, preferably 0.005-0.2: 1.
In a further improvement, when the reducing agent is hydrogen, the reaction is carried out at 1 to 10 atmospheres, preferably 1 to 3 atmospheres; when the reducing agent is ammonium formate or formic acid/triethylamine, the feeding ratio of the reducing agent to the compound (II) is 1.8-8:1, preferably 1.8-5: 1; when the reducing agent is methanol, ethanol or isopropanol, the mass ratio of the reducing agent to the compound (II) is 1-100:1, preferably 1-10: 1; the reaction temperature is selected from 0-150 ℃, preferably 20-130 ℃; the reaction time is 0.5 to 48 hours, preferably 1 to 24 hours.
Compared with the prior art, the invention has the following beneficial effects: (1) the invention has simple and convenient purification, high product content and almost no inorganic salt; (2) the invention has good reaction selectivity and high yield; (3) the method has the advantages of simple and easy operation, stable process, easy control, convenient treatment after reaction, good product yield and high purity, and can be economically and conveniently used for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are intended to be purely exemplary of the invention. These examples are not meant to impose any limitation on the invention. It will be apparent that those skilled in the art can make various changes and modifications to the present invention within the scope and spirit of the present invention. It is to be understood that the invention is intended to cover such alternatives and modifications as may be included within the scope of the appended claims.
The starting material N (T) -methyl-L-histidine benzyl ester used in the present invention can be conveniently prepared by reference to CN108727269A and Synthetic Commun.1986,16,1515-1516 and the like.
Example 1 Synthesis of N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (τ) -methyl-L-histidine benzyl ester
N (T) -methyl-L-histidine benzyl ester (10g, 39mmol) and benzyloxycarbonyl-beta-alanine (10.3g, 46mmol) were dissolved in 100mL of dichloromethane and, after addition of diisopropylethylamine (8.4g, 65mmol), HOBt (5.3g, 39mmol), EDCI (9.0g, 46mmol) were added at 20-30 ℃ and stirred for 5 hours at 20-30 ℃; the TLC detection shows that the reaction is finished. Adding water, stirring, removing water phase, washing organic phase with saturated ammonium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, concentrating, and recrystallizing with ethyl acetate/n-heptane. Filtering, and drying under reduced pressure to obtain 13.9g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (tau) -methyl-L-histidine benzyl ester. The molar yield was 78%.1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝7.7Hz,1H),7.49(d,J＝1.1Hz,1H),7.42–7.26(m,10H),7.18(t,J＝5.7Hz,1H),6.65(d,J＝1.1Hz,1H),5.17–5.06(m,2H),5.01(s,2H),4.56(td,J＝8.3,6.0Hz,1H),3.51(s,3H),3.17(q,J＝7.0Hz,2H),3.09–2.99(m,1H),2.99–2.88(m,1H),2.31(td,J＝7.1,1.5Hz,2H).
Example 2 Synthesis of N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (τ) -methyl-L-histidine benzyl ester
N (T) -methyl-L-histidine benzyl ester (10g, 39mmol) and benzyloxycarbonyl-beta-alanine (10.3g, 46mmol) were dissolved in 100mL of dichloromethane, triethylamine (6.6g, 65mmol), HOBt (5.3g, 39mmol), EDCI (9.0g, 46mmol) were added at 20-30 ℃ and after the addition was completed, stirring was carried out at 20-30 ℃ for 5 hours; the TLC detection shows that the reaction is finished. Adding water, stirring, removing water phase, washing organic phase with saturated ammonium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, concentrating, and recrystallizing with ethyl acetate/n-heptane. Filtering, drying under reduced pressure to obtain white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (tau)14.1g of benzyl-methyl-L-histidine ester with a molar yield of 79%.1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝7.7Hz,1H),7.49(d,J＝1.1Hz,1H),7.42–7.26(m,10H),7.18(t,J＝5.7Hz,1H),6.65(d,J＝1.1Hz,1H),5.17–5.06(m,2H),5.01(s,2H),4.56(td,J＝8.3,6.0Hz,1H),3.51(s,3H),3.17(q,J＝7.0Hz,2H),3.09–2.99(m,1H),2.99–2.88(m,1H),2.31(td,J＝7.1,1.5Hz,2H).
Example 3 Synthesis of N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (τ) -methyl-L-histidine benzyl ester
N (T) -methyl-L-histidine benzyl ester (10g, 39mmol) and benzyloxycarbonyl-beta-alanine (10.3g, 46mmol) were dissolved in 100mL dioxane and 1, 5-diazabicyclo [4.3.0] was added at 20-30 deg.C]Nonan-5-ene (13.5g, 109.2mmol), dicyclohexylcarbodiimide (11.4g, 55.2mmol), after the addition, stirring at 20-30 ℃ for 5 hours; the TLC detection shows that the reaction is finished. After concentration, water and dichloromethane were added, the aqueous phase was separated, the organic phase was washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, and after concentration, it was recrystallized from ethyl acetate/n-heptane. Filtering, and drying under reduced pressure to obtain 13.9g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (tau) -methyl-L-histidine benzyl ester with the molar yield of 78%.1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝7.7Hz,1H),7.49(d,J＝1.1Hz,1H),7.42–7.26(m,10H),7.18(t,J＝5.7Hz,1H),6.65(d,J＝1.1Hz,1H),5.17–5.06(m,2H),5.01(s,2H),4.56(td,J＝8.3,6.0Hz,1H),3.51(s,3H),3.17(q,J＝7.0Hz,2H),3.09–2.99(m,1H),2.99–2.88(m,1H),2.31(td,J＝7.1,1.5Hz,2H).
Example 4 Synthesis of N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (τ) -methyl-L-histidine benzyl ester
N (T) -methyl-L-histidine benzyl ester (10g, 39mmol) and benzyloxycarbonyl-beta-alanine (10g, 39mmol)3g, 46mmol) was dissolved in 100mL 2-methyltetrahydrofuran and 1, 4-diazabicyclo [2.2.2] was added at 20-30 deg.C]Octane (14.0g, 124.8mmol), N' -diisopropylcarbodiimide (14.2g, 69mmol), after the addition, was stirred at 20-30 ℃ for 5 hours; the TLC detection shows that the reaction is finished. Adding water, stirring, removing water phase, washing organic phase with saturated ammonium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, concentrating, and recrystallizing with ethyl acetate/n-heptane. Filtering, and drying under reduced pressure to obtain 13.7g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (tau) -methyl-L-histidine benzyl ester with the molar yield of 77%.1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝7.7Hz,1H),7.49(d,J＝1.1Hz,1H),7.42–7.26(m,10H),7.18(t,J＝5.7Hz,1H),6.65(d,J＝1.1Hz,1H),5.17–5.06(m,2H),5.01(s,2H),4.56(td,J＝8.3,6.0Hz,1H),3.51(s,3H),3.17(q,J＝7.0Hz,2H),3.09–2.99(m,1H),2.99–2.88(m,1H),2.31(td,J＝7.1,1.5Hz,2H).
Example 5 Synthesis of N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (τ) -methyl-L-histidine benzyl ester
N (T) -methyl-L-histidine benzyl ester (10g, 39mmol) and benzyloxycarbonyl-beta-alanine (10.3g, 46mmol) were dissolved in 100mL 2-methyltetrahydrofuran, triethylamine (g, 124.8mmol) and carbonyldiimidazole (11.2g, 69mmol) were added at 20-30 ℃ and after the addition was completed, the mixture was stirred at 20-30 ℃ for 5 hours; the TLC detection shows that the reaction is finished. Adding water, stirring, removing water phase, washing organic phase with saturated ammonium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, concentrating, and recrystallizing with ethyl acetate/n-heptane. Filtering, and drying under reduced pressure to obtain 14.1g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (tau) -methyl-L-histidine benzyl ester with 79 percent of molar yield.1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝7.7Hz,1H),7.49(d,J＝1.1Hz,1H),7.42–7.26(m,10H),7.18(t,J＝5.7Hz,1H),6.65(d,J＝1.1Hz,1H),5.17–5.06(m,2H),5.01(s,2H),4.56(td,J＝8.3,6.0Hz,1H),3.51(s,3H),3.17(q,J＝7.0Hz,2H),3.09–2.99(m,1H),2.99–2.88(m,1H),2.31(td,J＝7.1,1.5Hz,2H).
Example 6 Synthesis of N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (τ) -methyl-L-histidine benzyl ester
N (T) -methyl-L-histidine benzyl ester (10g, 39mmol) and benzyloxycarbonyl-beta-alanine (10.3g, 46mmol) were dissolved in 100mL of dichloromethane, HOBt (5.3g, 39mmol), EDCI (9.0g, 46mmol) were added at 20-30 ℃ and after the addition was completed, stirring was carried out at 70-80 ℃ for 12 hours; the TLC detection shows that the reaction is finished. Adding water, stirring, removing water phase, washing organic phase with saturated ammonium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, concentrating, and recrystallizing with ethyl acetate/n-heptane. Filtering, and drying under reduced pressure to obtain 13.9g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (tau) -methyl-L-histidine benzyl ester with the molar yield of 78%.1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝7.7Hz,1H),7.49(d,J＝1.1Hz,1H),7.42–7.26(m,10H),7.18(t,J＝5.7Hz,1H),6.65(d,J＝1.1Hz,1H),5.17–5.06(m,2H),5.01(s,2H),4.56(td,J＝8.3,6.0Hz,1H),3.51(s,3H),3.17(q,J＝7.0Hz,2H),3.09–2.99(m,1H),2.99–2.88(m,1H),2.31(td,J＝7.1,1.5Hz,2H).
Example 7 Synthesis of N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (τ) -methyl-L-histidine benzyl ester
Dissolving benzyloxycarbonyl-beta-alanine (10g, 45mmol) in 100mL of dichloromethane, adding N-methylmorpholine (10g, 99mmol) and isobutyl chloroformate (6.3g, 46mmol) at-10-0 ℃, reacting at-10-0 ℃ for half an hour after the addition is finished, adding a dichloromethane solution (30mL) of N (tau) -methyl-L-histidine benzyl ester (14g, 54mmol), naturally heating to 20-30 ℃, and stirring for 5 hours; the TLC detection shows that the reaction is finished. Adding water for quenching, stirring, removing water phase, washing organic phase with saturated ammonium chloride water solution, saturated sodium bicarbonate water solution, and saturated sodium chloride water solution, concentrating, and recrystallizing with ethyl acetate/n-heptane. Filtering, and drying under reduced pressure to obtain white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (tau) -methyl-L-histidine benzyl ester 16.7g with the molar yield of 80%.
Example 8 Synthesis of N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. tau.) -methyl-L-histidine benzyl ester
Dissolving benzyloxycarbonyl-beta-alanine (10g, 45mmol) in 100mL of acetonitrile, adding diisopropylethylamine (4.85g, 37.5mmol) and ethyl chloroformate (5.86g, 54mmol) at-10 to 0 ℃, reacting at-10 to 0 ℃ for half an hour after the addition, adding an acetonitrile solution (30mL) of N (tau) -methyl-L-histidine benzyl ester (7.8g, 30mmol), naturally heating to 20-30 ℃, and stirring for 24 hours; the TLC detection shows that the reaction is finished. Dichloromethane and water were added, the aqueous phase was separated, the organic phase was washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, concentrated, and recrystallized from ethyl acetate/n-heptane. Filtering, and drying under reduced pressure to obtain white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (tau) -methyl-L-histidine benzyl ester 16.9g with the molar yield of 81%.
Example 9 Synthesis of N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. tau.) -methyl-L-histidine benzyl ester
Dissolving carbobenzoxy-beta-alanine (10g, 45mmol) in 100mL of N-methylpyrrolidone, adding pyridine (2.67g, 33.8mmol) and pivaloyl chloride (6.5g, 54mmol) at the temperature of-10-0 ℃, reacting for half an hour at the temperature of-10-0 ℃ after the addition is finished, adding N-methylpyrrolidone solution (30mL) of N (tau) -methyl-L-histidine benzyl ester (5.85g, 22.5mmol), naturally heating to 70-80 ℃, and stirring for 12 hours; the TLC detection shows that the reaction is finished. Dichloromethane and water were added, the aqueous phase was separated, the organic phase was washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, concentrated, and recrystallized from ethyl acetate/n-heptane. Filtering, and drying under reduced pressure to obtain white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (tau) -methyl-L-histidine benzyl ester 16.7g with the molar yield of 80%.
Example 10 Synthesis of N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (τ) -methyl-L-histidine benzyl ester
Dissolving benzyloxycarbonyl-beta-alanine (10g, 45mmol) in 100mL of N, N-dimethylformamide, adding 4-dimethylaminopyridine (12.1g, 99mmol) and methyl chloroformate (4.35g, 46mmol) at-10-0 ℃, reacting at-10-0 ℃ for half an hour, adding a solution (30mL) of N (tau) -methyl-L-histidine benzyl ester (14g, 54mmol) in N, N-dimethylformamide, and naturally heating to 20-30 ℃ and stirring for 5 hours; the TLC detection shows that the reaction is finished. Dichloromethane and water were added, the aqueous phase was separated, the organic phase was washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution, concentrated, and recrystallized from ethyl acetate/n-heptane. Filtering, and drying under reduced pressure to obtain 17.1g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (tau) -methyl-L-histidine benzyl ester with the molar yield of 82%.
Example 11 Synthesis of N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. tau.) -methyl-L-histidine benzyl ester
Dissolving carbobenzoxy-beta-alanine (10g, 45mmol) in 100mL of diethoxymethane, adding 1, 8-diazabicyclo [5.4.0] undec-7-ene (15.0g, 99mmol) and isopropyl chloride (5.6g, 46mmol) at-10-0 ℃, reacting for half an hour at-10-0 ℃, adding a diethoxymethane solution (30mL) of N (tau) -methyl-L-histidine benzyl ester (14g, 54mmol), naturally heating to 20-30 ℃, and stirring for 5 hours; the TLC detection shows that the reaction is finished. Adding water, stirring, removing water phase, washing organic phase with saturated ammonium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, concentrating, and recrystallizing with ethyl acetate/n-heptane. Filtering, and drying under reduced pressure to obtain white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (tau) -methyl-L-histidine benzyl ester 16.5g with the molar yield of 79%.
Example 12 Synthesis of N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. tau.) -methyl-L-histidine benzyl ester
N (T) -methyl-L-histidine benzyl ester hydrochloride (10g, 34mmol) and benzyloxycarbonyl-beta-alanine (10.3g, 46mmol) were dissolved in 100mL of dichloromethane and diisopropylethylamine (13.2g, 102mmol), HOBt (5.3g, 39mmol), EDCI (9.0g, 46mmol) were added at 20-30 ℃ and after completion of addition, stirring was carried out for 5 hours at 20-30 ℃; the TLC detection shows that the reaction is finished. Adding water, stirring, removing water phase, washing organic phase with saturated ammonium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution, concentrating, and recrystallizing with ethyl acetate/n-heptane. Filtering, and drying under reduced pressure to obtain 13.9g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (tau) -methyl-L-histidine benzyl ester. The molar yield was 88%.1H NMR(400MHz,DMSO-d6)δ8.48(d,J＝7.7Hz,1H),7.49(d,J＝1.1Hz,1H),7.42–7.26(m,10H),7.18(t,J＝5.7Hz,1H),6.65(d,J＝1.1Hz,1H),5.17–5.06(m,2H),5.01(s,2H),4.56(td,J＝8.3,6.0Hz,1H),3.51(s,3H),3.17(q,J＝7.0Hz,2H),3.09–2.99(m,1H),2.99–2.88(m,1H),2.31(td,J＝7.1,1.5Hz,2H).
Example 13 Synthesis of anserine
N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. tau.) -methyl-L-histidine benzyl ester (10g, 22mmol) in MeOH/H2O (50mL/50mL), 10 w% Pd/C (1g) was added, and the mixture was reacted at 40 to 50 ℃ for 24 hours under a hydrogen atmosphere (1 atm). Filtering, washing the filter cake with water, decolorizing the filtrate twice with active carbon, filtering,concentrating to dry, adding anhydrous ethanol (50mL), pulping at 60-70 deg.C for 2h, cooling to 20-30 deg.C, and filtering to obtain anserine (4.7g,20mmol) with yield of 90%. Chemical purity: 99.3 percent; chiral purity: 99.4 percent; residue: 0.07 percent.
Example 14 Synthesis of anserine
N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. tau.) -methyl-L-histidine benzyl ester (10g, 22mmol) in MeOH/H2To O (50mL/50mL), palladium black (1g) was added, and the mixture was reacted at 40 to 50 ℃ for 24 hours under a hydrogen atmosphere (2 atm). Filtering, washing the filter cake with water, decolorizing the filtrate twice with active carbon, filtering, concentrating to dryness, adding anhydrous ethanol (50mL), pulping at 60-70 deg.C for 2h, cooling to 20-30 deg.C, and filtering to obtain anserine (4.8g,20.4mmol) with yield of 92%. Chemical purity: 99.7 percent; chiral purity: 99.5 percent; residue: 0.09 percent.
Example 15 Synthesis of anserine
N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. tau.) -methyl-L-histidine benzyl ester (10g, 22mmol) in MeOH/H2To O (50mL/50mL) were added palladium hydroxide (0.06g) and methanol (10g), and the mixture was reacted at 70 to 80 ℃ for 24 hours. Filtering, washing the filter cake with water, decolorizing the filtrate twice with active carbon, filtering, concentrating to dryness, adding anhydrous ethanol (50mL), pulping at 60-70 deg.C for 2h, cooling to 20-30 deg.C, and filtering to obtain anserine (4.7g,20mmol) with yield of 90%. Chemical purity: 99.7 percent; chiral purity: 99.5 percent; residue: 0.09 percent.
EXAMPLE 16 Synthesis of anserine
N (alpha) - (3- ((benzyloxy)Carbonyl) amino) propylcarbonyl) -N (tau) -methyl-L-histidine benzyl ester (10g, 22mmol) in MeOH/H2To O (50mL/50mL), 10% palladium hydroxide on carbon (2.6g) and isopropanol (100g) were added and the mixture was reacted at 70 to 80 ℃ for 24 hours. Filtering, washing the filter cake with water, decolorizing the filtrate twice with active carbon, filtering, concentrating to dryness, adding anhydrous ethanol (50mL), pulping at 60-70 deg.C for 2h, cooling to 20-30 deg.C, and filtering to obtain anserine (4.7g,20mmol) with yield of 90%. Chemical purity: 99.7 percent; chiral purity: 99.5 percent; residue: 0.09 percent.
Example 17 Synthesis of anserine
N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. tau.) -methyl-L-histidine benzyl ester (10g, 22mmol) in MeOH/H2To O (50mL/50mL), 10% palladium hydroxide/carbon (2.6g) and ethanol (50g) were added and the mixture was reacted at 70 to 80 ℃ for 24 hours. Filtering, washing the filter cake with water, decolorizing the filtrate twice with active carbon, filtering, concentrating to dryness, adding anhydrous ethanol (50mL), pulping at 60-70 deg.C for 2h, cooling to 20-30 deg.C, and filtering to obtain anserine (4.7g,20mmol) with yield of 90%. Chemical purity: 99.7 percent; chiral purity: 99.5 percent; residue: 0.09 percent.
EXAMPLE 18 Synthesis of anserine
N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. tau.) -methyl-L-histidine benzyl ester (10g, 22mmol) in MeOH/H2To O (50mL/50mL), Raney Ni (1g) was added, and the mixture was reacted at 20 to 30 ℃ for 24 hours under a hydrogen atmosphere (3 atm). Filtering, washing the filter cake with water, decolorizing the filtrate twice with active carbon, filtering, concentrating to dryness, adding anhydrous ethanol (50mL), pulping at 60-70 deg.C for 2h, cooling to 20-30 deg.C, and filtering to obtain anserine (4.8g,20mmol) with yield of 93%. Chemical purity: 99.5 percent; chiral purity: 99.6 percent; residue: 0.09 percent.
EXAMPLE 19 Synthesis of anserine
N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. tau.) -methyl-L-histidine benzyl ester (10g, 22mmol) in MeOH/H2To O (50mL/50mL), Raney Ni (1g) was added, and the mixture was reacted at 20 to 30 ℃ for 24 hours under a hydrogen atmosphere (3 atm). Filtering, washing the filter cake with water, decolorizing the filtrate twice with active carbon, filtering, concentrating to dryness, adding anhydrous ethanol (50mL), pulping at 60-70 deg.C for 2h, cooling to 20-30 deg.C, and filtering to obtain anserine (4.8g,20mmol) with yield of 93%. Chemical purity: 99.5 percent; chiral purity: 99.5 percent; residue: 0.08 percent.
EXAMPLE 20 Synthesis of anserine
N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. tau.) -methyl-L-histidine benzyl ester (10g, 22mmol) was dissolved in ethanol (50mL), Raney Ni (2g) and ammonium formate (39.6mmol) were added and reacted at 70-80 ℃ for 12 h. Filtering, washing the filter cake with water, decolorizing the filtrate twice with active carbon, filtering, concentrating to dryness, adding anhydrous ethanol (50mL), pulping at 60-70 deg.C for 2h, cooling to 20-30 deg.C, and filtering to obtain anserine (4.9g,20.4mmol) with yield of 95%. Chemical purity: 99.5 percent; chiral purity: 99.6 percent; residue: 0.09 percent.
Example 21 Synthesis of anserine
N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. tau.) -methyl-L-histidine benzyl ester (10g, 22mmol) was dissolved in tetrahydrofuran (50mL), Raney Ni (0.05g) and formic acid/triethylamine (110mmol) were added, and the mixture was reacted at 120 ℃ and 130 ℃ for 24 hours. Filtering, washing the filter cake with water, decolorizing the filtrate twice with active carbon, filtering, concentrating to dryness, adding anhydrous ethanol (50mL), pulping at 60-70 deg.C for 2h, cooling to 20-30 deg.C, and filtering to obtain anserine (4.8g,20mmol) with yield of 93%. Chemical purity: 99.5 percent; chiral purity: 99.6 percent; residue: 0.09 percent.
Claims (10)
1. A preparation method of an anserine intermediate shown in a formula (II) is characterized by comprising the following steps: condensing compound (III) with compound (IV) in a solvent in the presence/absence of a base to give compound (II) according to the following reaction formula:
2. the method for preparing anserine intermediate represented by formula (II) according to claim 1, wherein the method comprises forming mixed anhydride by reacting compound (III) with chloroformate compound comprising one or more of isobutyric acid chloroformate, ethyl chloroformate, methyl chloroformate or isopropyl chloroformate or pivaloyl chloride, and condensing the mixed anhydride with compound (IV) to obtain compound (II); the feeding molar ratio of the chloroformate or pivaloyl chloride to the compound (IV) is 0.6-1.5:1, preferably 0.9-1.2: 1.
3. The method for preparing anserine intermediate represented by formula (II) according to claim 2, which comprises condensing compound (III) with compound (IV) in the presence of a condensing agent comprising one or more of carbonyldiimidazole, dicyclohexylcarbodiimide, N' -diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride to obtain compound (II); the feeding molar ratio of the condensing agent to the compound (IV) is 0.6-5:1, preferably 0.9-1.5: 1.
4. The method for preparing anserine intermediate represented by the formula (II) according to claim 1, wherein the base is one or more of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, trimethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, 4-diazabicyclo [2.2.2] octane, preferably carbon trisethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, one or more of 4-diazabicyclo [2.2.2] octane; preferably one or more of carbocyclylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 5-diazabicyclo [4.3.0] non-5-ene or 1, 4-diazabicyclo [2.2.2] octane; the solvent is selected from benzene, toluene, chlorobenzene, xylene, isopropylbenzene, acetonitrile, benzonitrile, ethyl acetate, isopropyl acetate, 2-butanone, acetone, 1, 2-dimethyl-2-imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl ammonium phosphate, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, pyridine, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, t-butanol, t-amyl alcohol, polyethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1, 2-propylene glycol, diethoxymethane, dioxane, methyl t-butyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-hexane, cyclohexane, dichloromethane, toluene, ethyl acetate, isopropyl alcohol, ethylene glycol, t-butyl alcohol, t-amyl alcohol, One or more of 1, 2-dichloroethane, or chloroform; preferably one or more of toluene, dichloromethane, acetonitrile, ethylene glycol dimethyl ether, diethoxymethane, dioxane, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, tetrahydrofuran or 2-methyltetrahydrofuran.
5. The method for preparing anserine intermediate represented by formula (II) according to claim 1, wherein the feeding molar ratio of compound (IV) to compound (III) is 0.6-3: 1; preferably 0.8-2: 1; when the compound (III) is a free base, the feeding molar ratio of the base to the compound (III) is 0.6-5:1, preferably 0.8-2: 1; when compound (III) is the hydrochloride salt, the molar ratio of the base to compound (III) charged is from 2.6 to 7:1, preferably from 2.8 to 4: 1; the reaction temperature is-78-150 ℃, and preferably-10-130 ℃; the reaction time is 0.5 to 36 hours, preferably 1 to 24 hours.
6. An anserine intermediate compound (II) of the formula:
7. a method for preparing anserine (I) from a compound (II), which is characterized in that the compound (II) reacts in a solvent and a reducing agent in the presence of a catalyst to obtain the compound (I), namely the anserine, and the reaction equation is as follows:
8. the method for preparing anserine (I) from compound (II) according to claim 7, wherein the catalyst is one or more of palladium on carbon, palladium black, palladium hydroxide/carbon or Raney nickel; the reducing agent is one or more of hydrogen, ammonium formate, formic acid/triethylamine, ethanol, methanol or isopropanol; the solvent is selected from benzene, toluene, chlorobenzene, xylene, isopropylbenzene, acetonitrile, benzonitrile, ethyl acetate, isopropyl acetate, 2-butanone, acetone, 1, 2-dimethyl-2-imidazolone, dimethyl sulfoxide, dimethyl sulfone, sulfolane, hexamethyl ammonium phosphate, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, pyridine, methanol, ethanol, isopropanol, N-butanol, ethylene glycol, t-butanol, t-amyl alcohol, polyethylene glycol, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, 1, 2-propylene glycol, diethoxymethane, dioxane, methyl t-butyl ether, isopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, N-hexane, cyclohexane, dichloromethane, toluene, ethyl acetate, isopropyl alcohol, ethylene glycol, t-butyl alcohol, t-amyl alcohol, One or more of 1, 2-dichloroethane, chloroform, or water; preferably one or more of methanol, ethanol, tetrahydrofuran, ethyl acetate or water.
9. The method for preparing anserine (I) from compound (II) according to claim 8, wherein when the catalyst is one or more of palladium carbon, palladium black, palladium hydroxide/carbon, the mass ratio of Pd content in the catalyst to the amount of compound (II) charged is 0.001-0.5:1, preferably 0.005-0.2: 1; when the catalyst is Raney nickel, the mass ratio of the catalyst to the compound (II) is 0.001-0.5:1, preferably 0.005-0.2: 1.
10. The process for preparing anserine (I) from compound (II) according to claim 9, characterized in that, when the reducing agent is hydrogen, the reaction is carried out at 1-10 atmospheres, preferably 1-3 atmospheres; when the reducing agent is ammonium formate or formic acid/triethylamine, the feeding ratio of the reducing agent to the compound (II) is 1.8-8:1, preferably 1.8-5: 1; when the reducing agent is methanol, ethanol or isopropanol, the mass ratio of the reducing agent to the compound (II) is 1-100:1, preferably 1-10: 1; the reaction temperature is selected from 0-150 ℃, preferably 20-130 ℃; the reaction time is 0.5 to 48 hours, preferably 1 to 24 hours.
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| CN108997187A (en) * | 2018-07-13 | 2018-12-14 | 南京纽邦生物科技有限公司 | A kind of preparation method of N (π)-methyl-L-histidine derivative and its application in synthesis whale carnosine |
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| CN108997187A (en) * | 2018-07-13 | 2018-12-14 | 南京纽邦生物科技有限公司 | A kind of preparation method of N (π)-methyl-L-histidine derivative and its application in synthesis whale carnosine |
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