CN112876417A - Synthesis method of carnosine - Google Patents
Synthesis method of carnosine Download PDFInfo
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- CN112876417A CN112876417A CN202110193769.XA CN202110193769A CN112876417A CN 112876417 A CN112876417 A CN 112876417A CN 202110193769 A CN202110193769 A CN 202110193769A CN 112876417 A CN112876417 A CN 112876417A
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- water
- reaction
- compound
- histidine
- chloropropionyl chloride
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- QRYRORQUOLYVBU-VBKZILBWSA-N Carnosic acid Natural products CC([C@@H]1CC2)(C)CCC[C@]1(C(O)=O)C1=C2C=C(C(C)C)C(O)=C1O QRYRORQUOLYVBU-VBKZILBWSA-N 0.000 title claims abstract description 14
- 108010087806 Carnosine Proteins 0.000 title claims abstract description 14
- CQOVPNPJLQNMDC-UHFFFAOYSA-N N-beta-alanyl-L-histidine Natural products NCCC(=O)NC(C(O)=O)CC1=CN=CN1 CQOVPNPJLQNMDC-UHFFFAOYSA-N 0.000 title claims abstract description 14
- CQOVPNPJLQNMDC-ZETCQYMHSA-N carnosine Chemical compound [NH3+]CCC(=O)N[C@H](C([O-])=O)CC1=CNC=N1 CQOVPNPJLQNMDC-ZETCQYMHSA-N 0.000 title claims abstract description 14
- 229940044199 carnosine Drugs 0.000 title claims abstract description 14
- 238000001308 synthesis method Methods 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 32
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 claims abstract description 25
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229940126062 Compound A Drugs 0.000 claims abstract description 20
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 17
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 13
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical group [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000011049 filling Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000005191 phase separation Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 238000000354 decomposition reaction Methods 0.000 abstract description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 34
- 229960002885 histidine Drugs 0.000 description 26
- 239000012071 phase Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 210000002027 skeletal muscle Anatomy 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- BVGKKICUUAFHFE-UHFFFAOYSA-N 3-iodopropanoyl chloride Chemical compound ClC(=O)CCI BVGKKICUUAFHFE-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 108030007222 Carnosine synthases Proteins 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 150000002411 histidines Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 210000001503 joint Anatomy 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 210000003411 telomere Anatomy 0.000 description 1
- 102000055501 telomere Human genes 0.000 description 1
- 108091035539 telomere Proteins 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- 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
Abstract
The invention belongs to the field of organic synthesis, and discloses a carnosine synthesis method, which comprises the following steps: s1, reacting histidine with 3-chloropropionyl chloride to obtain a compound A; s2, aminating the compound A;
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthetic method of carnosine.
Background
Carnosine is a natural dipeptide consisting of beta-alanine and histidine and is naturally present in many tissues of the body, especially in muscle and brain tissues. Carnosine is synthesized by carnosine synthase mainly in skeletal muscle, cardiac muscle and certain specific brain regions. The first vertebrate skeletal muscle was discovered and studied for its physicochemical properties in 1900 in russian scholars Glewitsch and Amirad zhibi, and in recent years, the physiological functions of them have been studied.
Carnosine has a wide range of effects, such as antioxidation, metal ion chelation, acid-base buffering, telomere shortening inhibition, mitochondrial injury inhibition, glycosylation resistance, tumor resistance and the like. In animal experimental research, the carnosine is found to play a role in a plurality of diseases related to the old, such as promoting wound healing, being beneficial to Alzheimer disease, Parkinson disease, cerebral apoplexy and diabetic nephropathy, and the like. Carnosine was first used extensively in the health and dietary fields. As the skin is taken as the outermost organ of the body and firstly reflects the aging of the body, the skin is more and more concerned, the carnosine is more and more emphasized as an antioxidant and anti-aging product in the cosmetic application field at present, and the market demand is increased year by year.
The existing synthesis method has long route and low yield, some methods use expensive reagents (such as noble metal catalysts and 3-iodopropionyl chloride) to cause high cost, and the formed explosive intermediate compound has safety risk. It is therefore necessary to develop new routes for the synthesis of carnosine.
Disclosure of Invention
The invention aims to provide a method for synthesizing carnosine, which has high yield, low cost and few steps.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method of carnosine synthesis comprising the steps of:
s1, reacting histidine with 3-chloropropionyl chloride to obtain a compound A;
s2, aminating the compound A;
further, the reaction solvent of step S1 is tetrahydrofuran and water.
Further, the volume ratio of the tetrahydrofuran to the water is 1: 2 to 10.
Further, the step S1 adds an inorganic weak base.
Further, the inorganic weak base is sodium bicarbonate, sodium carbonate, potassium carbonate or potassium bicarbonate.
Furthermore, the dosage of the weak inorganic base is 3-8 times of the mole number of histidine.
Further, the molar ratio of histidine to 3-chloropropionyl chloride is 1: 2-5; the reaction temperature of the step S1 is 0-5 ℃.
Further, the step S1 is: adding histidine into tetrahydrofuran and water at 0-5 ℃, adding sodium bicarbonate, adding 3-chloropropionyl chloride under the stirring condition, keeping the temperature at 0-5 ℃ for reaction till the reaction is complete, standing for phase separation, washing an organic phase with salt water, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain a compound A.
In general recognition, acyl chloride is easily decomposed in water, so when a reaction solvent is selected, an organic solvent is considered, an aqueous phase system is not considered, but histidine is not dissolved in the organic solvent at all, DMF is not dissolved, and even DMSO is only slightly dissolved, so that the reaction is difficult to carry out, the reaction efficiency and the yield are not required at all, and for the reaction, histidine can be derivatized to solve the problem of solubility, or acyl chloride is replaced by other active ester reagents which are not easily decomposed.
The inventor unexpectedly finds that 3-chloropropionyl chloride has stronger stability in an aqueous solution added with inorganic weak base, 3-chloropropionyl chloride still exists in a large amount and is rarely decomposed after being continuously stirred for one week, and on the basis, a two-phase reaction system of dissolving histidine in water and dissolving 3-chloropropionyl chloride in THF is designed, and an inorganic solvent is added to stabilize the 3-chloropropionyl chloride, so that the butt joint of the histidine and the 3-chloropropionyl chloride is realized with high yield.
Further, the step S2 is ammoniated with ammonia water and ammonia gas.
Further, the molar ratio of the ammonia water to the compound A is 10-20: 1.
further, the step S2 is: adding the compound A and ammonia water into a high-pressure reaction kettle, vacuumizing, filling ammonia gas to 0.2-0.5 MPa, heating to 50-80 ℃ for complete reaction, removing the ammonia gas and the solvent, adding water and ethanol, and filtering and concentrating the precipitated solid to obtain the product.
On the other hand, compound a is a key intermediate of the reaction.
The invention has the following beneficial effects:
1. the first step of reaction is carried out in an organic solvent-water two-phase reaction, the problem that histidine is difficult to dissolve in an organic solvent is thoroughly solved by replacing the organic solvent with water, and the organic solvent is completely or partially replaced by the water, so that the method has advantages in cost and environmental protection.
2. The first step of reaction is carried out in an organic solvent-water two-phase reaction, the dosage of the organic solvent is less than that of water, and the small amount of the organic solvent can slow down the decomposition speed of the 3-chloropropionyl chloride in the water, so that the 3-chloropropionyl chloride can completely react with histidine before being completely decomposed. In addition, by utilizing the characteristic that THF can be dissolved in water, 3-chloropropionyl chloride dissolved in THF and histidine dissolved in water can be fully contacted and reacted, and meanwhile, the generated product continuously enters an organic phase, because the amount of THF is small, 3-chloropropionyl chloride is further forced out to react with histidine, a virtuous cycle is formed, and the reaction is promoted to be carried out.
3. In the organic solvent-water two-phase reaction, inorganic weak base such as sodium bicarbonate is added, so that hydrogen chloride generated in the system can be neutralized, and the inner salt of histidine can be destroyed to free amino, thereby being beneficial to the reaction. And meanwhile, the excessive sodium bicarbonate is added, so that the histidine salt is forced into a THF-water two-phase system, and the reaction is facilitated.
4. The raw material histidine does not need protection of a protecting group, so that the steps of protecting group application and protecting group removal are avoided, the synthetic route is shorter, the energy consumption is reduced, the raw material cost is reduced, and the environmental pollution is favorably reduced.
5. The cost of the reagents and raw materials used in the invention is low, wherein 3-chloropropionyl chloride is very cheap, and each kilogram of the 3-chloropropionyl chloride is only about fifty yuan, so histidine is more important for determining the cost. There are two reactive sites on histidine: considering that 3-chloropropionyl chloride is decomposed more or less, the nitrogen at the 3-position and the alpha-amino on the imidazole need to be added with at least 2 equivalents of 3-chloropropionyl chloride, so as to ensure the complete reaction of histidine and facilitate the separation and purification.
6. In the second step, the ammonia water is used for replacing organic ammonia solution, the reaction speed is higher, the efficiency is higher, the problem of incomplete reaction is avoided, and propionyl is removed while substrate amination is realized in the ammonia water through one-pot boiling; the amino substitution reaction of chlorine is realized under a pressurized state.
7. The method has simple post-treatment, can obtain the product by simple washing, filtering and the like, and has the advantages of mild reaction conditions, short route, economic steps and high product yield.
Detailed Description
The present invention will be further described with reference to the following specific examples. The following parts are all parts by weight.
Example 1
The first step is as follows: adding 15g (0.0620mol, 1eq) of L-histidine into 10mL of tetrahydrofuran and 50mL of water at 0-5 ℃, adding 26g (1.5476mol, 5eq) of sodium bicarbonate, stirring for 30min, slowly dropwise adding 20g (0.3937mol, 2.5eq) of 3-chloropropionyl chloride, keeping the temperature at 0-5 ℃ for 5h after dropwise adding, keeping the L-histidine reaction complete by TLC, standing for 30min for phase separation, washing the tetrahydrofuran phase with 50mL of saturated common salt water, drying with anhydrous sodium sulfate, evaporating to dryness at 50 ℃ under reduced pressure to obtain yellow oily matter, and performing column chromatography to obtain 18.5g (0.0552mol) of the compound A with the molar yield of 89%.
Characterization data:1HNMR(400MHz,MeOD):δ8.12(s,1H),6.51(s,1H),4.45-4.49(m,1H),3.76(t,4H),3.31-3.36(dd,2H),2.86(t,4H)；13CNMR(400MHz,MeOD):172.3188,171.5703,169.5647,131.9984,131.5282,117.3620,41.0465,40.7454,40.3309,40.1765,40.0269,31.2832。
the second step is that: adding 18g of the compound A into a high-pressure reaction kettle, adding 80mL of 20 wt% ammonia water, vacuumizing, filling ammonia gas to 0.3MPa, heating to 60 ℃, carrying out heat preservation reaction for 8 hours, tracking the raw material by TLC to react completely, extracting excessive ammonia gas, evaporating the solvent to obtain a crude product, adding 5mL of deionized water and 20mL of ethanol, separating out a white solid, and filtering to obtain 10.5g of a product with the molar yield of 86%.
Characterization data:1HNMR(400MHz,MeOD):δ7.61(s,1H),6.86(s,1H),4.36-4.38(m,1H),3.08-3.16(m,2H),3.01-3.06(dd,1H),2.85-2.90(dd,1H),2.51-2.59(t,2H)。
example 2
The first step is as follows: adding 5kg (32.26mol, 1eq) of L-histidine into 1L of tetrahydrofuran and 10L of water at 0-5 ℃, adding 2.168kg (8eq) of sodium bicarbonate, stirring for 120min, slowly dropwise adding 20.48kg (5eq) of 3-chloropropionyl chloride, keeping the temperature at 0-5 ℃ after dropwise adding, reacting for 10h, tracking the L-histidine by TLC to completely react, standing for 60min for phase separation, washing the tetrahydrofuran phase with 5L of saturated saline solution, drying with anhydrous sodium sulfate, and evaporating under reduced pressure below 50 ℃ to dryness to obtain a yellow oily compound A.
The second step is that: adding the compound A obtained in the first step into a high-pressure reaction kettle, adding 95L of 20 wt% ammonia water, vacuumizing, filling ammonia gas to 0.5MPa, heating to 60 ℃, carrying out heat preservation reaction for 18h, tracking the raw material by TLC to react completely, extracting redundant ammonia gas, evaporating the solvent to obtain a crude product, adding 1L of deionized water and 5L of ethanol, separating out a white solid, and filtering to obtain 5.176kg of a product, wherein the molar yield of the two steps is 71%.
The yield is not obviously reduced by the method test, which shows that the method is suitable for industrial production and does not need column chromatography and other steps.
Example 3
The first step is as follows: adding 3mol (1eq) of L-histidine into 500mL of tetrahydrofuran and 1L of water at 0-5 ℃, adding 9mol (3eq) of sodium carbonate, stirring for 60min, slowly dropwise adding 6mol (2eq) of 3-chloropropionyl chloride, keeping the temperature at 0-5 ℃ after dropwise adding, reacting for 8h, tracking by TLC that the L-histidine is completely reacted, standing for 30min for phase separation, washing the tetrahydrofuran phase with 1L of saturated saline solution, drying with anhydrous sodium sulfate, and evaporating under reduced pressure below 50 ℃ to dryness to obtain a yellow oily compound A.
The second step is that: adding the compound A obtained in the first step into a high-pressure reaction kettle, adding 6L of 20 wt% ammonia water, vacuumizing, filling ammonia gas to 0.4MPa, heating to 80 ℃, carrying out heat preservation reaction for 14h, tracking the raw material by TLC to react completely, extracting excessive ammonia gas, evaporating the solvent to obtain a crude product, adding 200mL of deionized water and 800mL of ethanol, separating out a white solid, and filtering to obtain 522g of a product, wherein the molar yield of the two steps is 77%.
Example 4
The first step is as follows: adding 1mol (1eq) of L-histidine into 100mL of tetrahydrofuran and 800mL of water at 0-5 ℃, adding 6mol (6eq) of potassium bicarbonate, stirring for 30min, slowly dropwise adding 4mol (4eq) of 3-chloropropionyl chloride, keeping the temperature at 0-5 ℃ for reacting for 5h after dropwise adding, tracking by TLC that the L-histidine completely reacts, standing for 30min for phase separation, washing the tetrahydrofuran phase with 400mL of saturated saline solution, drying with anhydrous sodium sulfate, and evaporating to dryness at the temperature of below 50 ℃ under reduced pressure to obtain a yellow oily compound A.
The second step is that: adding the compound A obtained in the first step into a high-pressure reaction kettle, adding 3L of 20 wt% ammonia water, vacuumizing, filling ammonia gas to 0.2MPa, heating to 50 ℃, carrying out heat preservation reaction for 10 hours, tracking the raw material by TLC to react completely, extracting excessive ammonia gas, evaporating the solvent to obtain a crude product, adding 100mL of deionized water and 300mL of ethanol, separating out a white solid, and filtering to obtain 169.5g of a product, wherein the molar yield of the two steps is 75%.
The above description is only an embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (10)
1. A method of carnosine synthesis comprising the steps of:
s1, reacting histidine with 3-chloropropionyl chloride to obtain a compound A;
s2, aminating the compound A;
2. the method according to claim 1, wherein the reaction solvent of step S1 is tetrahydrofuran and water.
3. The method according to claim 2, wherein the volume ratio of tetrahydrofuran to water is 1: 2 to 10.
4. The method according to any one of claims 1 to 3, wherein step S1 is performed by adding an inorganic weak base.
5. The method of claim 4, wherein the weak inorganic base is sodium bicarbonate, sodium carbonate, potassium carbonate, or potassium bicarbonate.
6. The process according to claim 1, characterized in that the molar ratio of histidine to 3-chloropropionyl chloride is 1: 2-5; the reaction temperature of the step S1 is 0-5 ℃.
7. The method according to claim 1, wherein the step S1 is: adding histidine into tetrahydrofuran and water at 0-5 ℃, adding sodium bicarbonate, adding 3-chloropropionyl chloride under the stirring condition, keeping the temperature at 0-5 ℃ for reaction till the reaction is complete, standing for phase separation, washing an organic phase with salt water, drying with anhydrous sodium sulfate, and evaporating to dryness under reduced pressure to obtain a compound A.
8. The method as claimed in claim 1, wherein the step S2 is ammoniated with ammonia water and ammonia gas.
9. The method according to claim 8, wherein the molar ratio of the ammonia water to the compound A is 10-20: 1.
10. the method according to claim 1, wherein the step S2 is: adding the compound A and ammonia water into a high-pressure reaction kettle, vacuumizing, filling ammonia gas to 0.2-0.5 MPa, heating to 50-80 ℃ for complete reaction, removing the ammonia gas and the solvent, adding water and ethanol, and filtering the precipitated solid to obtain the product.
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| CN105636442A (en) * | 2013-10-17 | 2016-06-01 | 美国陶氏益农公司 | Processes for the preparation of pesticidal compounds |
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