CN117510352A - Synthesis method of D-2, 3-diaminopropionic acid - Google Patents
Synthesis method of D-2, 3-diaminopropionic acid Download PDFInfo
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- CN117510352A CN117510352A CN202311480692.XA CN202311480692A CN117510352A CN 117510352 A CN117510352 A CN 117510352A CN 202311480692 A CN202311480692 A CN 202311480692A CN 117510352 A CN117510352 A CN 117510352A
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- PECYZEOJVXMISF-UWTATZPHSA-N 3-amino-D-alanine Chemical compound NC[C@@H](N)C(O)=O PECYZEOJVXMISF-UWTATZPHSA-N 0.000 title claims abstract description 10
- 238000001308 synthesis method Methods 0.000 title claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 42
- 239000007787 solid Substances 0.000 claims abstract description 29
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 239000002253 acid Substances 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 15
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 9
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 9
- 239000011734 sodium Substances 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 13
- 238000010992 reflux Methods 0.000 claims description 13
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 12
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical group [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- CRWJEUDFKNYSBX-UHFFFAOYSA-N sodium;hypobromite Chemical compound [Na+].Br[O-] CRWJEUDFKNYSBX-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 5
- 238000004090 dissolution Methods 0.000 claims 2
- 239000002994 raw material Substances 0.000 abstract description 9
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 229910052740 iodine Inorganic materials 0.000 abstract description 2
- 239000011630 iodine Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 description 43
- 238000003756 stirring Methods 0.000 description 34
- 238000010025 steaming Methods 0.000 description 17
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 13
- 239000007810 chemical reaction solvent Substances 0.000 description 10
- 230000001376 precipitating effect Effects 0.000 description 10
- 230000001105 regulatory effect Effects 0.000 description 10
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000006731 degradation reaction Methods 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000003529 anticholesteremic agent Substances 0.000 description 2
- 150000001541 aziridines Chemical class 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- WMSUFWLPZLCIHP-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 9h-fluoren-9-ylmethyl carbonate Chemical compound C12=CC=CC=C2C2=CC=CC=C2C1COC(=O)ON1C(=O)CCC1=O WMSUFWLPZLCIHP-UHFFFAOYSA-N 0.000 description 1
- HNQZURNWHYCIQZ-ZCFIWIBFSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-methylsulfonyloxypropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)COS(C)(=O)=O HNQZURNWHYCIQZ-ZCFIWIBFSA-N 0.000 description 1
- PEZNEXFPRSOYPL-UHFFFAOYSA-N (bis(trifluoroacetoxy)iodo)benzene Chemical compound FC(F)(F)C(=O)OI(OC(=O)C(F)(F)F)C1=CC=CC=C1 PEZNEXFPRSOYPL-UHFFFAOYSA-N 0.000 description 1
- PUMPMCQFSLQDOJ-UHFFFAOYSA-N 1-(2-acetyl-3-iodophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(I)=C1C(C)=O PUMPMCQFSLQDOJ-UHFFFAOYSA-N 0.000 description 1
- RBMGJIZCEWRQES-UHFFFAOYSA-N 4-amino-2-azaniumyl-4-oxobutanoate;hydrate Chemical compound O.OC(=O)C(N)CC(N)=O RBMGJIZCEWRQES-UHFFFAOYSA-N 0.000 description 1
- LHHRZPSINYXZPX-UHFFFAOYSA-N 7-chloro-2-(trifluoromethyl)quinoline Chemical compound C1=CC(Cl)=CC2=NC(C(F)(F)F)=CC=C21 LHHRZPSINYXZPX-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 description 1
- 229930195711 D-Serine Natural products 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- 108010029541 Laccase Proteins 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- JJSCUXAFAJEQGB-MRVPVSSYSA-N [(1r)-1-isocyanatoethyl]benzene Chemical compound O=C=N[C@H](C)C1=CC=CC=C1 JJSCUXAFAJEQGB-MRVPVSSYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- -1 aspartyl Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910000435 bromine oxide Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- 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 belongs to the field of compound synthesis, and particularly relates to a method for synthesizing D-2, 3-diaminopropionic acid. The method comprises the steps of firstly, reacting D-Boc asparagine and sodium hypohalite in a solvent to obtain an intermediate solution; then adjusting the pH value of the intermediate solution to 4-8, and removing the solvent to obtain a solid; finally, adding acid into the solid to react and purifying to obtain the catalyst; wherein the solvent in the step (1) is sodium hydroxide solution. The invention ensures that the reaction can be rapidly and fully carried out by controlling the temperature and time of the reaction process; the deprotected target product can be obtained in high yield by adding hydrochloric acid in stages. The method avoids using expensive iodine reagent, has the advantages of low cost and easy acquisition of raw materials, high overall reaction yield and low cost, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of compound synthesis, and particularly relates to a method for synthesizing D-2, 3-diaminopropionic acid.
Background
The D-2, 3-diaminopropionic acid has the following structure:the novel cholesterol-lowering drug MK0616 has wide application value as an unnatural amino acid, for example, a novel cholesterol-lowering drug MK0616 of moesadong is synthesized, a hemostatic compound D-dencichine is synthesized, and the like.
Some reports on the synthesis method of 2, 3-diaminopropionic acid are about, for example, using aspartic acid as raw material, and performing schmitt reaction to obtain 2, 3-diaminopropionic acid; the steps of ring opening, reduction, acidification and the like are carried out on aziridine derivatives and (R) - (+) -alpha-methylbenzyl isocyanate serving as raw materials by Uupender K.Nadir et al to obtain 2, 3-diaminopropionic acid; vicente Gotor et al likewise uses an aziridine derivative as a starting material to produce 2, 3-diaminopropionic acid via ring opening, hydrogenation reduction, protection of amine groups, acidification, and the like (see scheme 1).
In the method disclosed in Chinese patent CN109180532B, D-serine is taken as a raw material, D-Boc-serine is synthesized firstly, then the D-Boc-serine and methanesulfonyl chloride are subjected to ester formation in the presence of an acid binding agent, and Boc-D-serine methanesulfonate undergoes ammonolysis reaction to generate N-alpha-Boc-D-alpha, beta-diaminopropionic acid (see synthetic route 2).
Chinese patent CN113754551a discloses that the laccase solution is added to the weak acid solution at normal temperature, tryptophan and phenol are added to react for 2-4 hours under stirring to obtain diaminopropionic acid (see synthetic route 3).
The method disclosed above has the problems of low reaction conditions, difficult acquisition of starting materials, complicated synthetic route and the like, and is difficult to realize large-scale preparation of diaminopropionic acid.
The preparation of diaminopropionic acid by Huffman degradation reaction is a simple method, for example, chinese patent CN105439883A discloses that D-asparagine monohydrate is taken as a raw material, and reacts with 9-fluorenylmethyl-N-succinimidyl carbonate to obtain an intermediate, then the intermediate undergoes degradation reaction under the action of [ bis (trifluoroacetoxy) iodo ] benzene for 60 hours to obtain Fmoc-D-2, 3-diaminopropionic acid, and finally deprotection is carried out under the action of diethylamine to obtain D-2, 3-diaminopropionic acid; chinese patent CN102234240B discloses that huffman degradation of L-benzyloxycarbonyl asparayl under diacetyl iodobenzene gives Cbz-D-2, 3-diaminopropionic acid with a reaction time of 12 hours (see synthetic route 4).
The methods for preparing 2, 3-diaminopropionic acid by Huffman degradation reaction, which are disclosed in the prior art, all use expensive iodine reagent as raw materials, have higher cost and generally longer reaction time, and cause difficult industrialized implementation.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides a method for synthesizing D-2, 3-diaminopropionic acid, which has the advantages of easily available raw materials, low cost, short reaction time and high yield, and is suitable for industrial production.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a method for synthesizing D-2, 3-diaminopropionic acid comprises the following steps:
(1) Reacting D-Boc asparagine and sodium hypohalite in a solvent to obtain an intermediate solution; the method comprises the steps of carrying out a first treatment on the surface of the
(2) Adding acid into the intermediate solution, and removing the solvent to obtain a solid;
(3) Adding acid to the solid to react to obtain the catalyst;
further, in the step (1), the solvent is sodium hydroxide solution.
Further, the sodium hypohalite in the step (1) is sodium hypochlorite or sodium hypobromite.
Further, the molar ratio of D-Boc asparagine to sodium hypohalite in step (1) is 1:1.05-1.5.
Further, in the step (1), D-Boc asparagine is firstly mixed with a solvent, then sodium hypohalite solution is dropwise added at the temperature of-5-5 ℃ for reaction after the dropwise addition.
Further, the temperature of the reaction in the step (1) is 0-50 ℃ and the reaction time is 1-5 hours.
Further, the reaction in the step (1) is that the reaction is firstly carried out at 0-30 ℃ for 1-3 hours, and then the temperature is increased to 30-50 ℃ for 1-3 hours.
Further, the reaction in the step (1) is that the reaction is firstly carried out at 20-30 ℃ for 1-2 hours, and then the temperature is raised to 40-50 ℃ for 1-2 hours.
Further, in the step (2), the temperature of the intermediate solution is reduced to-5-5 ℃, the acid is concentrated hydrochloric acid, the pH value is adjusted to 4-8 after the acid is added, and the mass of the added concentrated hydrochloric acid is 1.05-1.5 times of the mass of the D-Boc aspartyl.
Further, in step (3), the acid is concentrated hydrochloric acid, hydrobromic acid or trifluoroacetic acid.
Further, in the step (3), the acid is concentrated hydrochloric acid.
Further, the molar ratio of acid to D-Boc asparagine in step (3) is 5-8:1.
further, the molar ratio of acid added to D-Boc asparagine in step (3) was 5.8:1.
further, the temperature of the reaction in the step (3) is 72-105 ℃, and the reaction is reflux reaction for 2-10 hours.
Further, the step (3) further comprises a purification step after the reaction, wherein the purification step comprises the steps of removing the solvent from the reacted solution, dissolving, crystallizing, filtering and drying.
Further, the solution is added with water, the crystallization is that ethanol or acetone is dripped at 20-50 ℃ to separate out solid, then the temperature is reduced to-5-5 ℃, and the temperature is kept for 0.5-2 hours.
The reaction route of the invention is as follows:
compared with the prior art, the invention has the following beneficial effects:
the synthesis method of the D-2, 3-diaminopropionic acid provided by the invention has the advantages of easily available raw materials, low cost, short reaction time and high yield, and is suitable for industrial production.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention. In addition, the raw materials related to the invention are common commercial products unless otherwise specified.
Example 1
Adding 40g D-Boc-aspartyl and 276ml of 2.5M sodium hydroxide solution into a four-mouth bottle, stirring and dissolving, cooling to 0 ℃, slowly dripping 166g of sodium hypochlorite solution (10%), heating to 25 ℃, preserving heat for 1 hour, heating to 50 ℃ and stirring for reaction, preserving heat for 1 hour, cooling to 0 ℃ after reaction, dripping 49g of concentrated hydrochloric acid, regulating pH value to 5, steaming the reaction solvent under reduced pressure to obtain a pale yellow solid, adding 100g of concentrated hydrochloric acid, stirring and heating to 105 ℃ (external temperature), refluxing for reaction for 6 hours, reacting, steaming the solvent under reduced pressure to dryness, adding 50ml of water-soluble clear, heating to 50 ℃, dripping 100ml of ethanol, precipitating solid, cooling to 0 ℃, preserving heat for 1 hour, filtering to obtain a wet product, and drying to obtain 20.6g (hydrochloride) of the product, wherein the yield is 85%.
Example 2
Adding 40g D-Boc-aspartyl and 276ml of 2.5M sodium hydroxide solution into a four-mouth bottle, stirring and dissolving, cooling to 0 ℃, slowly dripping 166g of sodium hypochlorite solution (10%), heating to 25 ℃, preserving heat for 1 hour, heating to 50 ℃ and stirring for reaction, preserving heat for 1 hour, cooling to 0 ℃ after reaction, dripping 49g of concentrated hydrochloric acid, regulating pH value to 5, steaming the reaction solvent under reduced pressure to obtain light yellow solid, adding 100g of concentrated hydrochloric acid, stirring and heating to 105 ℃ (external temperature), refluxing for reaction for 6 hours, reacting, steaming the solvent under reduced pressure to dryness, adding 50ml of water-soluble clear, heating to 50 ℃, dripping 100ml of acetone, precipitating solid, cooling to 0 ℃, preserving heat for 1 hour, filtering to obtain wet product, and drying to obtain 19.1g (hydrochloride) of the product, wherein the yield is 79%.
Example 3
Adding 40g D-Boc-asparagines and 276ml of 2.5M sodium hydroxide solution into a four-mouth bottle, stirring and dissolving, cooling to 0 ℃, slowly dripping 266g of sodium hypobromite solution (10 percent) into the four-mouth bottle (prepared by bromine and sodium hydroxide solution), heating to 25 ℃, preserving heat for 1 hour, heating to 50 ℃, stirring and reacting, preserving heat for 1 hour, cooling to 0 ℃, dripping 49g of concentrated hydrochloric acid into the four-mouth bottle, regulating the pH value to 5, steaming out the reaction solvent under reduced pressure to obtain light yellow solid, adding 100g of concentrated hydrochloric acid into the four-mouth bottle, stirring and heating to 105 ℃, refluxing and reacting for 6 hours, steaming out the solvent under reduced pressure to dryness, adding 50ml of water soluble clear, heating to 50 ℃, dripping 100ml of ethanol, precipitating solid, cooling to 0 ℃, preserving heat for 1 hour, filtering and obtaining a wet product, and drying to obtain 20.1g (hydrochloride) of the product with the yield of 83 percent.
Example 4
Adding 40g D-Boc-aspartyl and 276ml of 2.5M sodium hydroxide solution into a four-mouth bottle, stirring and dissolving, cooling to 0 ℃, slowly dripping 166g of sodium hypochlorite solution (10%), heating to 25 ℃, preserving heat for 1 hour, heating to 50 ℃ and stirring for reaction, preserving heat for 1 hour, cooling to 0 ℃ after reaction, dripping 49g of concentrated hydrochloric acid, regulating pH value to 5, steaming the reaction solvent under reduced pressure to obtain a pale yellow solid, adding 80g of 48% hydrobromic acid, stirring and heating to 105 ℃ (external temperature), refluxing for reaction for 6 hours, reacting, steaming the solvent under reduced pressure to dryness, adding 50ml of water-soluble clear, heating to 50 ℃, dripping 100ml of ethanol, precipitating solid, cooling to 0 ℃, preserving heat for 1 hour, filtering to obtain a wet product, and drying to obtain 26.6g (hydrobromide) of the product, wherein the yield is 83.8%.
Example 5
Adding 40g D-Boc-asparagine and 276ml of 2.5M sodium hydroxide solution into a four-mouth bottle, stirring and dissolving, cooling to-5 ℃, slowly dripping 166g of sodium hypochlorite solution (10%), heating to 25 ℃, preserving heat for 1 hour, heating to 50 ℃ and stirring for reaction, preserving heat for 1 hour, cooling to 5 ℃ after reaction, dripping 52g of concentrated hydrochloric acid, regulating pH to 4, evaporating the reaction solvent under reduced pressure to obtain light yellow solid, adding 80g of trifluoroacetic acid, stirring and heating to 72 ℃ for reflux reaction for 10 hours, reacting, evaporating the solvent under reduced pressure to dryness, adding 50ml of water solution, heating to 50 ℃, dripping 100ml of ethanol, separating out the solid, cooling to 5 ℃, preserving heat for 2 hours, filtering to obtain wet product, and drying to obtain 23.2g (trifluoroacetate) of the product, wherein the yield is 62%.
Example 6
Adding 40g D-Boc-aspartyl and 276ml of 2.5M sodium hydroxide solution into a four-mouth bottle, stirring and dissolving, cooling to 5 ℃, slowly dripping 166g of sodium hypochlorite solution (10%), heating to 20 ℃, preserving heat for 3 hours, heating to 40 ℃ and stirring for reaction, preserving heat for 2 hours, cooling to-5 ℃ after reaction, dripping 40g of concentrated hydrochloric acid, regulating pH value to 8, steaming the reaction solvent under reduced pressure to obtain a pale yellow solid, adding 138g of concentrated hydrochloric acid, stirring and heating to 90 ℃ (external temperature), refluxing for 2 hours, reacting, steaming the solvent under reduced pressure to dryness, adding 50ml of water-soluble clear, heating to 20 ℃, dripping 100ml of ethanol, precipitating solid, cooling to-5 ℃, preserving heat for 0.5 hours, filtering to obtain a wet product, and drying to obtain 15.8g (hydrochloride) of the product, wherein the yield is 65%.
Comparative example 1
Adding 40g D-Boc-aspartyl and 276ml of 2.5M potassium carbonate solution into a four-mouth bottle, stirring and dissolving, cooling to 0 ℃, slowly dripping 166g of sodium hypochlorite solution (10%), heating to 25 ℃, preserving heat for 1 hour, heating to 50 ℃ and stirring for reaction, preserving heat for 1 hour, cooling to 0 ℃ after reaction, dripping 49g of concentrated hydrochloric acid, regulating pH to 5, steaming the reaction solvent under reduced pressure to obtain a pale yellow solid, adding 100g of concentrated hydrochloric acid, stirring and heating to 105 ℃ (external temperature), refluxing for reaction for 6 hours, reacting, steaming the solvent under reduced pressure to dryness, adding 50ml of water-soluble clear, heating to 50 ℃, dripping 100ml of ethanol, precipitating solid, cooling to 0 ℃, preserving heat for 1 hour, filtering to obtain a wet product, and drying to obtain 3.2g (hydrochloride) of the product, wherein the yield is 13%.
Comparative example 2
Adding 40g D-Boc-aspartyl and 276ml of 2.5M sodium hydroxide solution into a four-mouth bottle, stirring and dissolving, cooling to 0 ℃, slowly dripping 166g of sodium hypochlorite solution (10%), heating to 25 ℃, preserving heat for 1 hour, heating to 50 ℃ and stirring for reaction, preserving heat for 1 hour, cooling to 0 ℃ after reaction, dripping 49g of concentrated hydrochloric acid, regulating pH value to 5, steaming the reaction solvent under reduced pressure to obtain a pale yellow solid, adding 100g of concentrated hydrochloric acid, stirring and heating to 60 ℃ (external temperature), preserving heat for reaction for 6 hours, reacting, steaming the solvent under reduced pressure to dryness, adding 50ml of water-soluble clear, heating to 50 ℃, dripping 100ml of ethanol, precipitating solid, cooling to 0 ℃, preserving heat for 1 hour, filtering to obtain a wet product, and drying to obtain 10.5g (hydrochloride) of the product, wherein the yield is 43%.
Comparative example 3
Adding 40g D-Boc-aspartyl and 276ml of 2.5M sodium hydroxide solution into a four-mouth bottle, stirring and dissolving, cooling to 0 ℃, slowly dripping 166g of sodium hypochlorite solution (10%), heating to 25 ℃, preserving heat for 1 hour, heating to 50 ℃ and stirring for reaction, preserving heat for 1 hour, cooling to 0 ℃ after reaction, dripping 49g of concentrated hydrochloric acid, regulating pH value to 5, steaming the reaction solvent under reduced pressure to obtain light yellow solid, adding 140g of 70% phosphoric acid, stirring and heating to 105 ℃ (external temperature), refluxing for reaction for 6 hours, reacting, steaming the solvent under reduced pressure to dryness, adding 50ml of water-soluble clear, heating to 50 ℃, dripping 100ml of ethanol, precipitating solid, cooling to 0 ℃, preserving heat for 1 hour, filtering to obtain a wet product, and drying to obtain 7.2g (phosphate) of the product, wherein the yield is 21%.
Comparative example 4
Adding 40g D-Boc-aspartyl and 276ml of 2.5M sodium hydroxide solution into a four-mouth bottle, stirring and dissolving, cooling to 0 ℃, slowly dripping 166g of sodium hypochlorite solution (10%), heating to 50 ℃ for stirring and reacting, preserving heat for 2 hours, cooling to 0 ℃, dripping 49g of concentrated hydrochloric acid, regulating the pH value to 5, evaporating the reaction solvent under reduced pressure to obtain a pale yellow solid, adding 100g of concentrated hydrochloric acid, stirring and heating to 105 ℃, carrying out reflux reaction for 6 hours, after the reaction, evaporating the solvent under reduced pressure to dryness, adding 50ml of water solution, heating to 50 ℃, dripping 100ml of ethanol, precipitating solid, cooling to 0 ℃, preserving heat for 1 hour, filtering to obtain a wet product, and drying to obtain 8.7g (hydrochloride) of a product, wherein the yield is 36%.
Comparative example 5
Adding 40g D-Boc-aspartyl and 276ml of 2.5M sodium hydroxide solution into a four-mouth bottle, stirring and dissolving, cooling to 0 ℃, slowly dripping 166g of sodium hypochlorite solution (10%), heating to 25 ℃, preserving heat for 1 hour, heating to 50 ℃ for stirring and reacting, preserving heat and reacting for 1 hour, adding 100g of concentrated hydrochloric acid, stirring and heating to 105 ℃ (external temperature), refluxing and reacting for 6 hours, decompressing and steaming to remove the solvent until dryness, adding 50ml of water solution, heating to 50 ℃, dripping 100ml of ethanol, precipitating solid, cooling to 0 ℃, preserving heat for 1 hour, filtering to obtain wet product, drying to obtain 13.3g (hydrochloride), and obtaining the product with the yield of 55%.
The foregoing examples illustrate only a few embodiments of the invention and are described in detail herein without thereby limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (10)
1. The synthesis method of the D-2, 3-diaminopropionic acid is characterized by comprising the following steps of:
(1) Reacting D-Boc asparagine and sodium hypohalite in a solvent to obtain an intermediate solution;
(2) Adding acid into the intermediate solution, and removing the solvent to obtain a solid;
(3) Adding acid to the solid to react, thus obtaining the product.
2. The method according to claim 1, wherein the solvent in the step (1) is sodium hydroxide solution, the sodium hypohalite is sodium hypochlorite or sodium hypobromite, the reaction temperature is 0-50 ℃, and the reaction time is 1-5 hours.
3. The synthetic method according to claim 2, wherein the reaction in step (1) is performed for 1-2 hours at 20-30 ℃ and then at 40-50 ℃ for 1-2 hours.
4. The method according to claim 1, wherein the molar ratio of D-Boc asparagine to sodium hypohalite in step (1) is 1:1.05-1.5, and step (1) is to mix D-Boc asparagine with solvent first, then drop sodium hypohalite solution at-5-5 ℃ and react.
5. The method according to claim 1, wherein in step (2), the temperature of the intermediate solution is reduced to-5 to 5 ℃, the acid is concentrated hydrochloric acid, the pH is adjusted to 4 to 8 after the acid is added, and the mass of the added concentrated hydrochloric acid is 1.05 to 1.5 times of the mass of D-Boc asparagine.
6. The synthetic method according to claim 1, wherein the acid in step (3) is concentrated hydrochloric acid, hydrobromic acid or trifluoroacetic acid, and the reaction temperature is 72-105 ℃.
7. The synthetic method of claim 1 wherein the reaction in step (3) is a reflux reaction, the reflux reaction being for a period of time ranging from 2 to 10 hours.
8. The synthetic method of claim 1, wherein the molar ratio of acid to D-Boc asparagine in step (3) is 5-8:1.
9. The synthetic method according to claim 1, wherein the step (3) further comprises a purification step after the reaction, wherein the purification step comprises removing a solvent from the reacted solution, dissolving, crystallizing, suction filtering, and drying.
10. The method according to claim 9, wherein the dissolution is water-added dissolution, the crystallization is dropping ethanol or acetone at 20-50 ℃ to precipitate solid, cooling to-5-5 ℃ and preserving heat for 0.5-2h.
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