CN112624976A - Whale carnosine intermediate, preparation method of whale carnosine and whale carnosine intermediate - Google Patents
Whale carnosine intermediate, preparation method of whale carnosine and whale carnosine intermediate Download PDFInfo
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- CN112624976A CN112624976A CN201910947863.2A CN201910947863A CN112624976A CN 112624976 A CN112624976 A CN 112624976A CN 201910947863 A CN201910947863 A CN 201910947863A CN 112624976 A CN112624976 A CN 112624976A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention provides a whale carnosine intermediate shown in a formula (II) and a preparation method thereof, wherein 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 a whale carnosine intermediate and a preparation method thereof. The invention also provides a method for preparing whale carnosine from the whale carnosine intermediate.
Background
Whale carnosine is an important natural histidine dipeptide and is widely distributed in the muscles of whale fish, snakes and dolphins. The whale carnosine is a natural physiological pH buffer besides functions of resisting oxidation and aging. Research shows that the whale carnosine has a much stronger ability to resist carnosine hydrolase than carnosine, and the hydrolysis rate is only one fifth of that of carnosine under the same condition. The whale carnosine has long half-life in tissues and organs, can reduce the dosage and the taking times, and has good application prospect. In recent years, the demand of whale carnosine in the fields of food and medicine is increasing, and the content of whale carnosine in muscle is very low, so that the development of an industrial preparation method of whale carnosine is particularly urgent.
In 1964, Rinderknecht et al reported that N (Pi) -methyl-L-histidine and phthaloyl protected alanine were subjected to condensation, hydrazinolysis and salt formation to prepare whale carnosine nitrate, and the obtained nitrate was exchanged with ion exchange resin to obtain whale carnosine, wherein the reaction route is shown as follows:
the yield of the condensation and hydrazinolysis salification steps of the route is only 30%, the operation is complicated, the whale carnosine free alkali can be obtained after ion resin exchange is needed, and the route is not suitable for commercial production.
In 2016 Toshiyuki Kan et al reported the following routes on Synlett2016,27, 2734-:
in the above route, raw and auxiliary materials are expensive, the optical purity of the product is low, and column chromatography used in the route cannot be industrialized; the whale carnosine is easy to dissolve in water and other solvents, the desalting difficulty is very high, and residues are found to be more than 30% when the desalting operation is repeated in a laboratory. Therefore, a synthetic route for preparing whale carnosine, which has the advantages of high content, simple and convenient operation, stable quality and suitability for industrial production, is urgently needed to be provided.
Disclosure of Invention
In order to solve the above technical problems, an object of the present invention is to provide a whale carnosine 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 a whale carnosine intermediate shown in a formula (II) comprises the following steps of condensing a compound (III) and a compound (IV) in a solvent in the presence/absence of alkali to obtain the 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 pivaloyl chloride or chloroformate compound to the compound (IV) is 0.6-1.5:1, preferably 0.8-1.2: 1; the feeding molar ratio of the condensing agent to the compound (IV) is 0.6-5:1, preferably 0.8-3: 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.
Another object of the invention is to provide a method for preparing whale carnosine (I) from 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:
reacting the compound (II) in a solvent in the presence of a catalyst in a reducing agent to obtain a compound (I), namely whale carnosine, 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 (π) -methyl-L-histidine benzyl ester used in the present invention can be conveniently prepared by reference to CN108997187A and Synthetic Commun.1986,16,1515-1516, etc.
Example 1 Synthesis of N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (π) -methyl-L-histidine benzyl ester
N (π) -methyl-L-histidine benzyl ester (10g, 39mmol) and benzyloxycarbonyl- β -alanine (10.3g, 46mmol) were dissolved in 100mAdding triethylamine (6.6g, 65mmol), HOBt (5.3g, 39mmol) and EDCI (9.0g, 46mmol) into L dichloromethane at 20-30 deg.C, and stirring at 20-30 deg.C for 5 hr; 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 13.4g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (pi) -methyl-L-histidine benzyl ester with the molar yield of 75%.1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝7.4Hz,1H),7.43(d,J＝1.3Hz,1H),7.42–7.30(m,8H),7.29(dd,J＝7.9,1.7Hz,2H),7.25(t,J＝5.6Hz,1H),6.77(d,J＝1.3Hz,1H),5.14–5.05(m,2H),5.02(s,2H),4.51(td,J＝7.7,5.9Hz,1H),3.53(s,3H),3.20(q,J＝6.3,5.8Hz,2H),2.85(qd,J＝14.6,6.9Hz,2H),2.31(dd,J＝8.1,6.4Hz,2H).
Example 2 Synthesis of N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (π) -methyl-L-histidine benzyl ester
N (π) -methyl-L-histidine benzyl ester (10g, 39mmol) and benzyloxycarbonyl- β -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 (14.2g, 69mmol), after the addition, stirring 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 14.0g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (pi) -methyl-L-histidine benzyl ester with the molar yield of 75%.1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝7.4Hz,1H),7.43(d,J＝1.3Hz,1H),7.42–7.30(m,8H),7.29(dd,J＝7.9,1.7Hz,2H),7.25(t,J＝5.6Hz,1H),6.77(d,J＝1.3Hz,1H),5.14–5.05(m,2H),5.02(s,2H),4.51(td,J＝7.7,5.9Hz,1H),3.53(s,3H),3.20(q,J＝6.3,5.8Hz,2H),2.85(qd,J＝14.6,6.9Hz,2H),2.31(dd,J＝8.1,6.4Hz,2H).
Example 3 Synthesis of N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (π) -methyl-L-histidine benzyl ester
N (π) -methyl-L-histidine benzyl ester (10g, 39mmol) and benzyloxycarbonyl- β -alanine (10.3g, 46mmol) were dissolved in 100mL 2-methyltetrahydrofuran and 1, 4-diazabicyclo [2.2.2] added at 20-30 deg.C]Octane (14.0g, 124.8mmol), N' -diisopropylcarbodiimide (11.6g, 92mmol), 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 13.2g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (pi) -methyl-L-histidine benzyl ester with the molar yield of 74%.1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝7.4Hz,1H),7.43(d,J＝1.3Hz,1H),7.42–7.30(m,8H),7.29(dd,J＝7.9,1.7Hz,2H),7.25(t,J＝5.6Hz,1H),6.77(d,J＝1.3Hz,1H),5.14–5.05(m,2H),5.02(s,2H),4.51(td,J＝7.7,5.9Hz,1H),3.53(s,3H),3.20(q,J＝6.3,5.8Hz,2H),2.85(qd,J＝14.6,6.9Hz,2H),2.31(dd,J＝8.1,6.4Hz,2H).
Example 4 Synthesis of N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. pi.) -methyl-L-histidine benzyl ester
N (π) -methyl-L-histidine benzyl ester (10g, 39mmol) and benzyloxycarbonyl- β -alanine (10.3g, 46mmol) were dissolved in 100mL 2-methyltetrahydrofuran, triethylamine (14.0g, 138mmol) and carbonyldiimidazole (11.2g, 69mmol) were added at 20-30 ℃ and after the addition was complete, 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, and mixing the organic phase with saturated ammonium chloride aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chlorideWashed with aqueous solution, concentrated and recrystallized from ethyl acetate/n-heptane. Filtering, and drying under reduced pressure to obtain 13.8g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (pi) -methyl-L-histidine benzyl ester with the molar yield of 78%.1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝7.4Hz,1H),7.43(d,J＝1.3Hz,1H),7.42–7.30(m,8H),7.29(dd,J＝7.9,1.7Hz,2H),7.25(t,J＝5.6Hz,1H),6.77(d,J＝1.3Hz,1H),5.14–5.05(m,2H),5.02(s,2H),4.51(td,J＝7.7,5.9Hz,1H),3.53(s,3H),3.20(q,J＝6.3,5.8Hz,2H),2.85(qd,J＝14.6,6.9Hz,2H),2.31(dd,J＝8.1,6.4Hz,2H).
Example 5 Synthesis of N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (π) -methyl-L-histidine benzyl ester
N (Pi) -methyl-L-histidine benzyl ester (10g, 39mmol) and benzyloxycarbonyl-beta-alanine (10.3g, 46mmol) were dissolved in 100mL of dichloromethane, HOBt (5.3g, 39mmol) and 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 14.0g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (pi) -methyl-L-histidine benzyl ester with the molar yield of 78%.1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝7.4Hz,1H),7.43(d,J＝1.3Hz,1H),7.42–7.30(m,8H),7.29(dd,J＝7.9,1.7Hz,2H),7.25(t,J＝5.6Hz,1H),6.77(d,J＝1.3Hz,1H),5.14–5.05(m,2H),5.02(s,2H),4.51(td,J＝7.7,5.9Hz,1H),3.53(s,3H),3.20(q,J＝6.3,5.8Hz,2H),2.85(qd,J＝14.6,6.9Hz,2H),2.31(dd,J＝8.1,6.4Hz,2H).
Example 6 Synthesis of N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. pi.) -methyl-L-histidine benzyl ester
Dissolving benzyloxycarbonyl-beta-alanine (10g, 45mmol) in 100mL of dichloromethane, adding N-methylmorpholine (10g, 99mmol) and isobutyrate chloroformate (6.3g, 46mmol) at-10 to 0 ℃, reacting at-10 to 0 ℃ for half an hour after the addition is finished, adding a dichloromethane solution (30mL) of benzyl N (pi) -methyl-L-histidine (14g, 54mmol), naturally heating to 20 to 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 (pi) -methyl-L-histidine benzyl ester 16.3g with the molar yield of 78%.
Example 7 Synthesis of N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. pi.) -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-10-0 ℃, reacting at-10-0 ℃ for half an hour after the addition is finished, adding an acetonitrile solution (30mL) of N (pi) -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. After concentration, 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, and after concentration, it was recrystallized from ethyl acetate/n-heptane. Filtering, and drying under reduced pressure to obtain 15.5g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (pi) -methyl-L-histidine benzyl ester with the molar yield of 74%.
Example 8 Synthesis of N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. pi.) -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 (5.43g, 45mmol) 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 (pi) -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. Adding water and dichloromethane, 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 15.6g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (pi) -methyl-L-histidine benzyl ester with the molar yield of 75%.
Example 9 Synthesis of N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. pi.) -methyl-L-histidine benzyl ester
Dissolving carbobenzoxy-beta-alanine (10g, 45mmol) in 100mLN, N-dimethylformamide, adding 4-dimethylaminopyridine (12.1g, 99mmol) and methyl chloroformate (4.35g, 46mmol) at-10-0 ℃, reacting for half an hour at-10-0 ℃, adding N (pi) -methyl-L-histidine benzyl ester (14g, 54mmol) in N, N-dimethylformamide (30mL), naturally heating to 20-30 ℃, and stirring for 5 hours; the TLC detection shows that the reaction is finished. Adding water and dichloromethane, 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 (pi) -methyl-L-histidine benzyl ester 16.3g with the molar yield of 78%.
Example 10 Synthesis of N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. pi.) -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 to 0 ℃, reacting for half an hour at-10 to 0 ℃ after the addition is finished, adding a diethoxymethane solution (30mL) of N (pi) -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 (pi) -methyl-L-histidine benzyl ester 16.3g with the molar yield of 78%.
Example 11 Synthesis of N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. pi.) -methyl-L-histidine benzyl ester
N (Pi) -methyl-L-histidine benzyl ester hydrochloride (10g, 34mmol) and benzyloxycarbonyl-beta-alanine (10.3g, 46mmol) were dissolved in 100mL of dichloromethane, triethylamine (10.3g, 102mmol), 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, and drying under reduced pressure to obtain 13.4g of white solid N (alpha) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (pi) -methyl-L-histidine benzyl ester with the molar yield of 85%.1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝7.4Hz,1H),7.43(d,J＝1.3Hz,1H),7.42–7.30(m,8H),7.29(dd,J＝7.9,1.7Hz,2H),7.25(t,J＝5.6Hz,1H),6.77(d,J＝1.3Hz,1H),5.14–5.05(m,2H),5.02(s,2H),4.51(td,J＝7.7,5.9Hz,1H),3.53(s,3H),3.20(q,J＝6.3,5.8Hz,2H),2.85(qd,J＝14.6,6.9Hz,2H),2.31(dd,J＝8.1,6.4Hz,2H).
Example 12 Synthesis of whale carnosine
N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (π) -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 filter cake with water, decolorizing filtrate with active carbon twice, 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 whale carnosine (4.7g,20mmol) with yield of 90%. Chemical purity: 99.7 percent; chiral purity: 99.5 percent; residue: 0.09 percent.1H NMR(400MHz,D2O)δ7.48(d,J＝1.4Hz,1H),6.83(d,J＝1.4Hz,1H),4.35(dd,J＝8.5,4.7Hz,1H),3.58(s,3H),3.16(td,J＝6.5,1.6Hz,2H),2.98(ddd,J＝14.9,4.8,0.8Hz,1H),2.83(dd,J＝14.9,8.5Hz,1H),2.70–2.50(m,2H).
Example 13 Synthesis of whale carnosine
N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (π) -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 filter cake with water, decolorizing filtrate with active carbon twice, 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 whale carnosine (4.8g,20.4mmol) with yield of 92%. Chemical purity: 99.7 percent; chiral purity: 99.5 percent; residue: 0.09 percent.1H NMR(400MHz,D2O)δ7.48(d,J＝1.4Hz,1H),6.83(d,J＝1.4Hz,1H),4.35(dd,J＝8.5,4.7Hz,1H),3.58(s,3H),3.16(td,J＝6.5,1.6Hz,2H),2.98(ddd,J＝14.9,4.8,0.8Hz,1H),2.83(dd,J＝14.9,8.5Hz,1H),2.70–2.50(m,2H).
Example 14 Synthesis of whale carnosine
N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (π) -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 filter cake with water, decolorizing filtrate with active carbon twice, 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 whale carnosine (4.7g,20mmol) with yield of 90%. Chemical purity: 99.7 percent; chiral purity: 99.5 percent; residue: 0.09 percent.1H NMR(400MHz,D2O)δ7.48(d,J＝1.4Hz,1H),6.83(d,J＝1.4Hz,1H),4.35(dd,J＝8.5,4.7Hz,1H),3.58(s,3H),3.16(td,J＝6.5,1.6Hz,2H),2.98(ddd,J＝14.9,4.8,0.8Hz,1H),2.83(dd,J＝14.9,8.5Hz,1H),2.70–2.50(m,2H).
Example 15 Synthesis of whale carnosine
N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (π) -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 filter cake with water, decolorizing filtrate with active carbon twice, 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 whale carnosine (4.7g,20mmol) with yield of 90%. Chemical purity: 99.7 percent; chiral purity: 99.5 percent; residue: 0.09 percent.1H NMR(400MHz,D2O)δ7.48(d,J＝1.4Hz,1H),6.83(d,J＝1.4Hz,1H),4.35(dd,J＝8.5,4.7Hz,1H),3.58(s,3H),3.16(td,J＝6.5,1.6Hz,2H),2.98(ddd,J＝14.9,4.8,0.8Hz,1H),2.83(dd,J＝14.9,8.5Hz,1H),2.70–2.50(m,2H).
EXAMPLE 16 Synthesis of whale carnosine
N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (π) -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 filter cake with water, decolorizing filtrate with active carbon twice, 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 whale carnosine (4.7g,20mmol) with yield of 90%. Chemical purity: 99.7 percent; chiral purity: 99.5 percent; residue: 0.09 percent.1H NMR(400MHz,D2O)δ7.48(d,J＝1.4Hz,1H),6.83(d,J＝1.4Hz,1H),4.35(dd,J＝8.5,4.7Hz,1H),3.58(s,3H),3.16(td,J＝6.5,1.6Hz,2H),2.98(ddd,J＝14.9,4.8,0.8Hz,1H),2.83(dd,J＝14.9,8.5Hz,1H),2.70–2.50(m,2H).
Example 17 Synthesis of whale carnosine
N (α) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (π) -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 filter cake with water, decolorizing 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 whale carnosine (4.8g,20mmol) with yield of 93%. Chemical purity: 99.5 percent; chiral purity: 99.6 percent; residue: 0.09 percent.
EXAMPLE 18 Synthesis of whale carnosine
N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. pi.) -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 filter cake with water, decolorizing filtrate with active carbon twice, 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 whale carnosine (4.9g,20.4mmol) with yield of 95%. Chemical purity: 99.5 percent; chiral purity: 99.6 percent; residue: 0.09 percent.
EXAMPLE 19 Synthesis of whale carnosine
N (. alpha.) - (3- ((benzyloxycarbonyl) amino) propylcarbonyl) -N (. pi.) -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 filter cake with water, decolorizing 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 whale carnosine (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 whale carnosine intermediate shown in 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 the whale carnosine intermediate represented by formula (II) according to claim 1, which comprises reacting compound (III) with a chloroformate compound comprising one or more of isobutyric acid chloroformate, ethyl chloroformate, methyl chloroformate or isopropyl chloroformate or pivaloyl chloride to form a mixed anhydride, and condensing the mixed anhydride with compound (IV) to obtain compound (II); the feeding molar ratio of the pivaloyl chloride or chloroformate compound to the compound (IV) is 0.6-1.5:1, preferably 0.8-1.2: 1.
3. The method for preparing whale carnosine 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 give compound (II); the feeding molar ratio of the condensing agent to the compound (IV) is 0.6-5:1, preferably 0.8-3: 1.
4. The method for preparing a cetamine carnosine 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 triethylamme, 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 whale carnosine intermediate represented by formula (II) according to claim 1, wherein the 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. A whale carnosine intermediate compound (II) having the formula:
7. a method for preparing whale carnosine (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 whale carnosine, and the reaction equation is as follows:
8. the process for preparing whale carnosine (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 whale carnosine (I) from compound (II) according to claim 8, wherein when the catalyst is one or more of palladium on carbon, palladium black, palladium hydroxide/carbon, the mass ratio of the Pd content in the catalyst to the charge amount of 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.
10. Process for the preparation of whale carnosine (I) from compound (II) according to claim 9, characterised 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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| CN101891686A (en) * | 2010-07-20 | 2010-11-24 | 吉尔生化（上海）有限公司 | Synthesizing method of N-beta-alanyl-(tau-methyl) histidine |
| US20180179511A1 (en) * | 2016-12-27 | 2018-06-28 | Tokai Bussan Co., Ltd. | Protein having synthetic activity for imidazole dipeptid and production method of imidazole dipeptide |
| 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 |
| CN109748875A (en) * | 2019-02-12 | 2019-05-14 | 南京纽邦生物科技有限公司 | A kind of preparation method of whale carnosine and its intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101891686A (en) * | 2010-07-20 | 2010-11-24 | 吉尔生化（上海）有限公司 | Synthesizing method of N-beta-alanyl-(tau-methyl) histidine |
| US20180179511A1 (en) * | 2016-12-27 | 2018-06-28 | Tokai Bussan Co., Ltd. | Protein having synthetic activity for imidazole dipeptid and production method of imidazole dipeptide |
| 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 |
| CN109748875A (en) * | 2019-02-12 | 2019-05-14 | 南京纽邦生物科技有限公司 | A kind of preparation method of whale carnosine and its intermediate |
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