CN114085161A - Intermediate for preparing 5-ALA & HCl and preparation method of 5-ALA & HCl - Google Patents
Intermediate for preparing 5-ALA & HCl and preparation method of 5-ALA & HCl Download PDFInfo
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- CN114085161A CN114085161A CN202110906365.0A CN202110906365A CN114085161A CN 114085161 A CN114085161 A CN 114085161A CN 202110906365 A CN202110906365 A CN 202110906365A CN 114085161 A CN114085161 A CN 114085161A
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- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 18
- 229950010481 5-aminolevulinic acid hydrochloride Drugs 0.000 claims abstract description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims abstract description 15
- ISOLMABRZPQKOV-UHFFFAOYSA-N diethyl 2-acetamidopropanedioate Chemical compound CCOC(=O)C(NC(C)=O)C(=O)OCC ISOLMABRZPQKOV-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229940126214 compound 3 Drugs 0.000 claims abstract description 11
- 229940125904 compound 1 Drugs 0.000 claims abstract description 7
- 229940125782 compound 2 Drugs 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 230000000911 decarboxylating effect Effects 0.000 claims abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 239000005457 ice water Substances 0.000 claims description 37
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 238000010992 reflux Methods 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 238000010438 heat treatment Methods 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000009835 boiling Methods 0.000 claims description 10
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 7
- LOLKAJARZKDJTD-UHFFFAOYSA-N 4-Ethoxy-4-oxobutanoic acid Chemical compound CCOC(=O)CCC(O)=O LOLKAJARZKDJTD-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims 2
- 238000004809 thin layer chromatography Methods 0.000 claims 2
- 238000003756 stirring Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 17
- DKMROQRQHGEIOW-UHFFFAOYSA-N Diethyl succinate Chemical compound CCOC(=O)CCC(=O)OCC DKMROQRQHGEIOW-UHFFFAOYSA-N 0.000 abstract description 10
- 230000007062 hydrolysis Effects 0.000 abstract description 9
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 230000009467 reduction Effects 0.000 abstract description 7
- 239000006227 byproduct Substances 0.000 abstract description 4
- 238000004440 column chromatography Methods 0.000 abstract description 4
- 238000006114 decarboxylation reaction Methods 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 3
- 238000004821 distillation Methods 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 238000007670 refining Methods 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 19
- 150000001875 compounds Chemical class 0.000 description 17
- 238000007792 addition Methods 0.000 description 16
- JOOXCMJARBKPKM-UHFFFAOYSA-N 4-oxopentanoic acid Chemical compound CC(=O)CCC(O)=O JOOXCMJARBKPKM-UHFFFAOYSA-N 0.000 description 10
- 229960002749 aminolevulinic acid Drugs 0.000 description 9
- 239000013078 crystal Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 230000031709 bromination Effects 0.000 description 5
- 238000005893 bromination reaction Methods 0.000 description 5
- 229940040102 levulinic acid Drugs 0.000 description 5
- 238000004611 spectroscopical analysis Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 238000005886 esterification reaction Methods 0.000 description 4
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 230000009435 amidation Effects 0.000 description 3
- 238000007112 amidation reaction Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 229940014800 succinic anhydride Drugs 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 208000009621 actinic keratosis Diseases 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000002428 photodynamic therapy Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- WXUAQHNMJWJLTG-VKHMYHEASA-N (S)-methylsuccinic acid Chemical compound OC(=O)[C@@H](C)CC(O)=O WXUAQHNMJWJLTG-VKHMYHEASA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- PDOSDCQRPAABHW-UHFFFAOYSA-N 4-oxo-4-propoxybutanoic acid Chemical compound CCCOC(=O)CCC(O)=O PDOSDCQRPAABHW-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- SZVDGKFPAMSDKN-UHFFFAOYSA-N furan;methanamine Chemical compound NC.C=1C=COC=1 SZVDGKFPAMSDKN-UHFFFAOYSA-N 0.000 description 1
- DDRPCXLAQZKBJP-UHFFFAOYSA-N furfurylamine Chemical compound NCC1=CC=CO1 DDRPCXLAQZKBJP-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- BYXYCUABYHCYLY-UHFFFAOYSA-N isoindole-1,3-dione;potassium Chemical compound [K].C1=CC=C2C(=O)NC(=O)C2=C1 BYXYCUABYHCYLY-UHFFFAOYSA-N 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- LYGJENNIWJXYER-BJUDXGSMSA-N nitromethane Chemical group [11CH3][N+]([O-])=O LYGJENNIWJXYER-BJUDXGSMSA-N 0.000 description 1
- 230000009935 nitrosation Effects 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 238000007539 photo-oxidation reaction Methods 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- 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
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
Abstract
The invention provides an intermediate for preparing 5-ALA & HCl and a preparation method of 5-ALA & HCl, comprising the steps of reacting a compound 1 with a compound 2 in an ether solvent to obtain a compound 3; hydrolyzing and decarboxylating the compound 3 by concentrated hydrochloric acid to obtain 5-aminolevulinic acid hydrochloride; the invention adopts conventional, easily obtained and cheap diethyl acetamidomalonate and ethyl succinate monoacyl chloride chemical raw materials to prepare the obtained intermediate, directly prepares 5-aminolevulinic acid hydrochloride by reacting with concentrated hydrochloric acid for hydrolysis and decarboxylation, directly removes impurities by a distillation method, can effectively reduce the production cost of the 5-aminolevulinic acid hydrochloride, reduces the refining steps, and has remarkable novelty and creativity. The method overcomes the defects that the 3-bromo by-product is removed by column chromatography or high vacuum rectification, the operation steps are complicated and the yield is low in the prior art, and has the advantages of short route, simple process, easiness in operation, high yield, reduction in production cost and suitability for industrial mass production.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis pharmacy, in particular to an intermediate for preparing 5-ALA & HCl and a preparation method of 5-ALA & HCl.
Background
Photodynamic therapy (PDT) is initiated in the seventies of the twentieth century, and has gradually become one of basic means for treating tumors due to development and progress of photosensitive substances and the like in recent years, 5-aminolevulinic acid hydrochloride (5-ALA & HCl) is a hydrochloride of a new generation photodynamic therapy medicament 5-aminolevulinic acid (5-ALA), and is clinically used for treating Actinic Keratosis (AK).
Although the structure of 5-aminolevulinic acid hydrochloride is simple, the synthesis is difficult, especially the process for industrial production can be carried out, and the main synthetic methods in the prior art are summarized as follows:
1. glycine is used as a raw material, and phthalic amidation, acylchlorination, condensation, decarboxylation and hydrolysis are carried out (J.chem.Soc. (1954,1820)).
2. Furanylmethylamine is used as a raw material, and phthalic amidation, photooxidation, reduction and hydrolysis are carried out (EP 607,952).
3. Furan methylamine is used as a raw material, and reduction, phthalic amidation, ruthenium catalytic oxidation and hydrolysis are carried out (EP 483,714).
4. Epichlorohydrin is used as a raw material, and the raw material comprises Gerberry reaction, bromination, oxidation, condensation, hydrolysis, decarboxylation and hydrolysis (J.org.chem. (1959,556)).
5. With levulinic acid as a raw material, bromination, guerberi reaction, hydrolysis (can. j. of Chem. (1974,3257); ball. de. soc. chimi. de France (1956,1750)).
6. Succinic anhydride is used as a raw material, and the raw material is subjected to monoesterification, acylchlorination, cyanation, reduction and hydrolysis (tetra. lett. (1984,2977)).
7. Levulinic acid is used as a raw material, and bromination, azidation and hydrogenolysis are performed (syn. Commun. (1994,2557)).
8. Succinic anhydride is used as a raw material, and mono-esterification, acyl chlorination, condensation, nitrosation, reduction and water are adopted (syn) (1999, 568).
9. Succinic anhydride is used as a raw material, and mono-esterification, acyl chlorination, imidization and nitromethane substitution hydrogenation reduction are carried out (syn, 1999,568).
From the above synthetic routes, there are disadvantages in these synthetic routes in that: if the routes of the route 4 and the route 8 are too long, the yield is not high, the equipment investment is large, and the cost is not too low even if the raw materials are cheap and easy to obtain; the routes such as the route 4 and the route 6 are short, but the used reagents are polluted greatly, and the routes such as the route 6 and the route 7 have the defect of poor safety; or too expensive raw materials as route 2, route 3 and route 9; or the conditions for operating as route 1 and route 2 are severe.
The most industrialized prospect in the prior art is the route 5, the reaction route is short, the raw materials are cheap, but the technical problem of the route in industrialization lies in the bromination and esterification step of levulinic acid, the target product 5-bit brominated product can be obtained in the product, the proportion of the non-target product 3-bit brominated product is also high, the side reaction is mainly separated and purified by a physical purification method and cannot be eliminated by controlling the reaction conditions, so the purification is separated by a column chromatography or high vacuum distillation method, the cost is high, the irritation of the brominated products is large, and the operator can be damaged.
CN1490305A discloses that the product of bromination esterification of levulinic acid can be directly subjected to the labyrinthine reaction without separation, and then purified by recrystallization, but the yield of the method is too low (7% in terms of levulinic acid), and a large amount of expensive potassium phthalimide salt is used, so that the production cost is high.
In production practice, through a large amount of analysis, all the literature and patent methods are physical methods, namely, a 3-brominated by-product is removed through column chromatography or high vacuum rectification, and a method for removing the by-product by using a chemical method is not reported.
Disclosure of Invention
In view of the above-mentioned drawbacks and problems of the prior art, the present invention provides an intermediate for the preparation of 5-ALA · HCl and a method for the preparation of 5-ALA · HCl, i.e. an intermediate for the synthesis of 5-aminolevulinic acid hydrochloride and a method for the preparation of 5-aminolevulinic acid hydrochloride thereof.
In order to achieve the purpose, the technical scheme provided by the invention is as follows:
an intermediate for preparing 5-aminolevulinic acid hydrochloride, which has the following structure:
wherein, R is chain hydrocarbon, including methyl, ethyl and propyl.
In the technical scheme, the compound 3 formed when R is ethyl is preferred, and the raw material of the succinic acid ethyl ester monoacyl chloride used for synthesizing the compound has higher cost advantage and is most suitable for commercial production.
A preparation method of 5-aminolevulinic acid hydrochloride comprises the following steps:
step one, reacting a compound 1 with a compound 2 in an ether solvent to obtain a compound 3;
step two, hydrolyzing and decarboxylating the compound 3 by concentrated hydrochloric acid to obtain 5-aminolevulinic acid hydrochloride;
the compound 1 is diethyl acetamidomalonate; the compound 2 is one of ethyl succinate monoacyl chloride, methyl succinate monoacyl chloride and propyl succinate monoacyl chloride, and the synthetic route is as follows.
In the technical scheme, in the step one, after potassium tert-butoxide is added in batches in a mixed solution of an ether solvent and a compound 1 in an ice-water bath, the ice-water bath is removed, the temperature is raised to about 25 ℃ and stirred for 2-3 hours, then the mixture is cooled to below 0 ℃ in the ice-water bath, a compound 2 is added, the dropping speed is controlled to be 0-10 ℃, the dropping is completed, the mixture is heated and refluxed for 4-5 hours, the TLC detection reaction is completed, the reaction solution is cooled to room temperature, the concentration is carried out, the concentrated solution is poured into the ice-water, the obtained solid is precipitated, filtered, washed with water and dried, and a compound 3 is obtained;
and step two, mixing the compound 3 with concentrated hydrochloric acid, heating to reflux, distilling off fractions with boiling points lower than 100 ℃ at normal pressure, continuously refluxing the residues until TLC shows that the reaction is complete, decoloring by using activated carbon, concentrating a water phase to obtain a white-like solid, and recrystallizing by using acetone and water in a ratio of 5:1 to obtain 5-aminolevulinic acid hydrochloride.
In the above technical scheme, the ether solvent includes anhydrous tetrahydrofuran, anhydrous diethyl ether, anhydrous isopropyl ether, and anhydrous methyl tert-butyl ether.
The invention adopts conventional, easily obtained and cheap diethyl acetamidomalonate and ethyl succinate monoacyl chloride chemical raw materials to prepare the obtained intermediate, directly prepares 5-aminolevulinic acid hydrochloride by reacting with concentrated hydrochloric acid for hydrolysis and decarboxylation, directly removes impurities by a distillation method, can effectively reduce the production cost of the 5-aminolevulinic acid hydrochloride, reduces the refining steps, and has remarkable novelty and creativity. The method overcomes the defects that the 3-bromo by-product is removed by column chromatography or high vacuum rectification, the operation steps are complicated and the yield is low in the prior art, and has the advantages of short route, simple process, easiness in operation, high yield, reduction in production cost and suitability for industrial mass production.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
An example of the preparation of a gel formulation as shown by way of example is as follows:
example 1
(1) In a 5 l dry four-necked flask, 2500 ml of anhydrous tetrahydrofuran and 434.4 g (2mol) of diethyl acetylaminomalonate were added, and 246.9 g (2.2mol) of potassium t-butoxide were added in portions in an ice-water bath (i.e., 0 ℃ C.). After the addition, the ice-water bath is removed, the temperature is raised to about 25 ℃, the mixture is stirred for 2 to 3 hours, then the mixture is cooled to below 0 ℃ by the ice-water bath, 316.2 g (2.1mol) of succinic acid ethyl ester monoacyl chloride is slowly dripped, and the dripping speed is controlled to enable the temperature to be 0 to 10 ℃. After the dropwise addition, heating and refluxing for 4-5 hours, and detecting by TLC to complete the reaction. The reaction was cooled to room temperature and concentrated. Pouring the concentrated solution into ice water, separating out a large amount of solid, filtering, washing with water and drying to obtain 3600 g of off-white compound, wherein the yield is 90.6%.
(2) And (3) adding 3600 g of the compound obtained in the last step and 2L of concentrated hydrochloric acid into a 5L four-mouth bottle, heating to reflux, distilling a fraction with the boiling point lower than 100 ℃ at normal pressure, continuously refluxing the residue until TLC shows that the reaction is complete, decoloring by using activated carbon, and concentrating a water phase to obtain a white-like solid. Recrystallization from acetone and water 5:1 gave 240 g of white crystals with a yield of 79.1%. mp: 149-152 ℃.
The spectral data are:
1HNMR(300M,DMSO)δ:2.50(2H,t,-CH2-),2.75(2H,t,-CH2-), 3.93(2H,s,-CH2NH2),8.40(3H,s,NH2HCl),12.3(1H,s,COOH)。
example 2
(1) In a 100 l dry glass reactor, 13.03 kg (60mol) of anhydrous tetrahydrofuran and diethyl acetylaminomalonate (60 l) are added, and 10.10 kg (90mol) of potassium tert-butoxide are added in portions after the temperature is lowered to below 0 ℃. After the addition, the temperature is raised to about 25 ℃, the mixture is stirred for 2 to 3 hours, then the mixture is frozen and cooled to below 0 ℃, 10.84 kg (72mol) of ethyl succinate monoacid chloride is slowly dripped, and the dripping speed is controlled to enable the temperature to be 0 to 10 ℃. After the dropwise addition, heating and refluxing for 4-5 hours, and detecting by TLC to complete the reaction. The reaction was cooled to room temperature and concentrated. Pouring the concentrated solution into ice water, separating out a large amount of solid, filtering, washing with water and drying to obtain 317.58 kg of off-white compounds, wherein the yield is 88.4%.
(2) Adding 317.58 kg of the compound obtained in the last step and 60 l of concentrated hydrochloric acid into a 100 l glass reaction kettle, heating to reflux, distilling off fraction with boiling point lower than 100 ℃ under normal pressure, continuously refluxing the remainder until TLC shows that the reaction is complete, decoloring by activated carbon, and concentrating the water phase to obtain a white-like solid. Recrystallizing with acetone and water at a ratio of 5:1 to obtain 7.45 kg of white crystals with a yield of 83.8 percent. mp 150-152 deg.C, the same spectrum data as example 1.
Example 3
(1) In a 10 liter dry four-necked flask, 651.6 g (3mol) of anhydrous ether and diethyl acetylaminomalonate were added, and 673.4 g (6mol) of potassium t-butoxide were added in portions in an ice-water bath (i.e., 0 ℃ C.). After the addition, the ice-water bath is removed, the temperature is raised to about 25 ℃, the mixture is stirred for 2 to 3 hours, then the mixture is cooled to below 0 ℃ by the ice-water bath, 677.6 g (4.5mol) of ethyl succinate monoacid chloride is slowly dropped, and the dropping speed is controlled to enable the temperature to be 0 to 10 ℃. After the dropwise addition, heating and refluxing for 4-5 hours, and detecting by TLC to complete the reaction. The reaction was cooled to room temperature and concentrated. The concentrated solution is poured into ice water, a large amount of solid is separated out, filtered, washed and dried to obtain 3868 g of off-white compound, and the yield is 87.3%.
(2) Adding 3868 g of the compound obtained in the previous step and 5 l of concentrated hydrochloric acid into a 10 l four-mouth bottle, heating to reflux, distilling a fraction with the boiling point lower than 100 ℃ under normal pressure, continuously refluxing the remainder until TLC shows that the reaction is complete, decoloring by using activated carbon, and concentrating a water phase to obtain a white-like solid. Recrystallization from acetone and water 5:1 gave 370 g of white crystals with a yield of 84.3%. mp: 149-151 ℃.
The spectroscopic data were as in example 1.
Example 3
(1) In a 10 liter dry four-necked flask, 781.9 g (3.6mol) of anhydrous isopropyl ether and diethyl acetylaminomalonate were added, and 606.1 g (5.4mol) of potassium t-butoxide were added in portions in an ice-water bath (i.e., 0 ℃ C.). After the addition, the ice-water bath is removed, the temperature is raised to about 25 ℃, the mixture is stirred for 2 to 3 hours, then the mixture is cooled to below 0 ℃ by the ice-water bath, 650.5 g (4.32mol) of ethyl succinate monoacid chloride is slowly dropped, and the dropping speed is controlled to enable the temperature to be 0 to 10 ℃. After the dropwise addition, heating and refluxing for 4-5 hours, and detecting by TLC to complete the reaction. The reaction was cooled to room temperature and concentrated. The concentrated solution is poured into ice water, a large amount of solid is separated out, filtered, washed and dried to obtain 31002 g of off-white compound, and the yield is 84.0%.
(2) Adding 31002 g of the compound obtained in the previous step and 5 l of concentrated hydrochloric acid into a 10 l four-mouth bottle, heating to reflux, distilling a fraction with the boiling point lower than 100 ℃ under normal pressure, continuously refluxing the remainder until TLC shows that the reaction is complete, decoloring by active carbon, and concentrating the water phase to obtain a white-like solid. Recrystallization from acetone and water 5:1 gave 432 g of white crystals with 85.3% yield. mp: 151-153 ℃.
The spectroscopic data were as in example 1.
Example 4
(1) In a 10 liter dry four-necked flask, 781.9 g (3.6mol) of anhydrous methyl t-butyl ether and diethyl acetylaminomalonate were added, and 606.1 g (5.4mol) of potassium t-butoxide were added in portions in an ice-water bath (i.e., 0 ℃ C.). After the addition, the ice-water bath is removed, the temperature is raised to about 25 ℃, the mixture is stirred for 2 to 3 hours, then the mixture is cooled to below 0 ℃ by the ice-water bath, 650.5 g (4.32mol) of ethyl succinate monoacid chloride is slowly dropped, and the dropping speed is controlled to enable the temperature to be 0 to 10 ℃. After the dropwise addition, heating and refluxing for 4-5 hours, and detecting by TLC to complete the reaction. The reaction was cooled to room temperature and concentrated. Pouring the concentrated solution into ice water, separating out a large amount of solid, filtering, washing with water and drying to obtain 3988 g of off-white compound, wherein the yield is 82.8%.
(2) Adding 3988 g of the compound obtained in the previous step and 5L of concentrated hydrochloric acid into a 10L four-mouth bottle, heating to reflux, distilling a fraction with the boiling point lower than 100 ℃ at normal pressure, continuously refluxing the remainder until TLC shows that the reaction is complete, decoloring by using activated carbon, and concentrating a water phase to obtain a white-like solid. Recrystallization from acetone and water 5:1 gave 422 g of white crystals with a yield of 84.5%. mp: 151-153 ℃.
The spectroscopic data were as in example 1.
Example 5
(1) In a 10 l dry four-necked flask, 781.9 g (3.6mol) of anhydrous tetrahydrofuran and diethyl acetylaminomalonate were added, and 489.6 g (7.2mol) of sodium ethoxide was added in portions in an ice-water bath (i.e., 0 ℃). After the addition, the ice-water bath is removed, the temperature is raised to about 25 ℃, the mixture is stirred for 2 to 3 hours, then the mixture is cooled to below 0 ℃ by the ice-water bath, 650.5 g (4.32mol) of ethyl succinate monoacid chloride is slowly dropped, and the dropping speed is controlled to enable the temperature to be 0 to 10 ℃. After the dropwise addition, heating and refluxing for 4-5 hours, and detecting by TLC to complete the reaction. The reaction was cooled to room temperature and concentrated. Pouring the concentrated solution into ice water, separating out a large amount of solid, filtering, washing with water and drying to obtain 3950 g of off-white compound, wherein the yield is 79.7%.
(2) Adding 3950 g of the compound obtained in the previous step and 5L of concentrated hydrochloric acid into a 10L four-mouth bottle, heating to reflux, distilling a fraction with the boiling point lower than 100 ℃ at normal pressure, continuously refluxing the remainder until TLC shows that the reaction is complete, decoloring by using activated carbon, and concentrating a water phase to obtain a white-like solid. Recrystallization from acetone and water 5:1 gave 412 g of white crystals with 85.8% yield. mp: 149-152 ℃.
The spectroscopic data were as in example 1.
Example 6
(1) In a 10 l dry four-necked flask, 781.9 g (3.6mol) of anhydrous tetrahydrofuran and diethyl acetylaminomalonate were added, and 388.8 g (7.2mol) of sodium methoxide was added in portions in an ice-water bath (i.e., 0 ℃). After the addition, the ice-water bath is removed, the temperature is raised to about 25 ℃, the mixture is stirred for 2 to 3 hours, then the mixture is cooled to below 0 ℃ by the ice-water bath, 650.5 g (4.32mol) of ethyl succinate monoacid chloride is slowly dropped, and the dropping speed is controlled to enable the temperature to be 0 to 10 ℃. After the dropwise addition, heating and refluxing for 4-5 hours, and detecting by TLC to complete the reaction. The reaction was cooled to room temperature and concentrated. Pouring the concentrated solution into ice water, separating out a large amount of solid, filtering, washing with water and drying to obtain 3900 g of a white-like compound, wherein the yield is 75.5%.
(2) And adding 3900 g of the compound obtained in the previous step and 5 l of concentrated hydrochloric acid into a 10-L four-mouth bottle, heating to reflux, distilling a fraction with the boiling point lower than 100 ℃ at normal pressure, continuously refluxing the remainder until TLC shows that the reaction is complete, decoloring by using activated carbon, and concentrating a water phase to obtain a white-like solid. Recrystallization from acetone and water 5:1 gave 395 g of white crystals in 86.8% yield. mp: 149-152 ℃.
The spectroscopic data were as in example 1.
Example 7
(1) In a 10 liter dry four-necked flask, 781.9 g (3.6mol) of anhydrous tetrahydrofuran and diethyl acetylaminomalonate were added, and 216 g (5.4mol) of 60% sodium hydride was added in portions in an ice water bath (i.e., 0 ℃). After the addition, the ice-water bath is removed, the temperature is raised to about 25 ℃, the mixture is stirred for 2 to 3 hours, then the mixture is cooled to below 0 ℃ by the ice-water bath, 650.5 g (4.32mol) of ethyl succinate monoacid chloride is slowly dropped, and the dropping speed is controlled to enable the temperature to be 0 to 10 ℃. After the dropwise addition, heating and refluxing for 4-5 hours, and detecting by TLC to complete the reaction. The reaction was cooled to room temperature and concentrated. The concentrated solution is poured into ice water, a large amount of solid is separated out, filtered, washed and dried to obtain 31058 g of off-white compound, and the yield is 88.7%.
(2) Adding 31058 g of the compound obtained in the previous step and 5 l of concentrated hydrochloric acid into a 10 l four-neck flask, heating to reflux, distilling off the fraction with the boiling point lower than 100 ℃ under normal pressure, continuously refluxing the residue until TLC shows that the reaction is complete, decolorizing with activated carbon, and concentrating the water phase to obtain the off-white solid.
Claims (4)
1. An intermediate for preparing 5-ALA & HCl has the following structure:
wherein, R is chain hydrocarbon, including methyl, ethyl and propyl.
2. A preparation method of 5-ALA & HCl is characterized by comprising the following steps: prepared using an intermediate as described in claim 1 for the preparation of 5-ALA-HCl;
the method comprises the following steps:
step one, reacting a compound 1 with a compound 2 in an ether solvent to obtain a compound 3;
step two, hydrolyzing and decarboxylating the compound 3 by concentrated hydrochloric acid to obtain 5-aminolevulinic acid hydrochloride;
the compound 1 is diethyl acetamidomalonate; the compound 2 is succinic acid ethyl ester monoacyl chloride.
3. The process for the preparation of 5-ALA-HCl as claimed in claim 2, wherein: adding potassium tert-butoxide into a mixed solution of an ether solvent and a compound 1 in an ice-water bath in batches, removing the ice-water bath, heating to about 25 ℃, stirring for 2-3 hours, cooling to below 0 ℃ by using the ice-water bath, adding a compound 2, controlling the dropping speed to enable the temperature to be 0-10 ℃, after the dropping is finished, heating and refluxing for 4-5 hours, detecting by TLC (thin layer chromatography) for complete reaction, cooling the reaction solution to room temperature, concentrating, pouring the concentrated solution into the ice water, separating out the obtained solid, filtering, washing with water and drying to obtain a compound 3;
and step two, mixing the compound 3 with concentrated hydrochloric acid, heating to reflux, distilling off fractions with boiling points lower than 100 ℃ at normal pressure, continuously refluxing the residues until TLC shows that the reaction is complete, decoloring by using activated carbon, concentrating a water phase to obtain a white-like solid, and recrystallizing by using acetone and water in a ratio of 5:1 to obtain 5-aminolevulinic acid hydrochloride.
4. The process for the preparation of 5-ALA-HCl as claimed in claim 3, wherein: the ether solvent comprises anhydrous tetrahydrofuran, anhydrous diethyl ether, anhydrous isopropyl ether and anhydrous methyl tert-butyl ether.
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| CN101891639A (en) * | 2009-05-20 | 2010-11-24 | 上海先导化学有限公司 | Method for preparing 5-aminolevulinic acid hydrochloride |
| CN102627573A (en) * | 2012-03-30 | 2012-08-08 | 山东大学 | Synthesis method for 5-aminolevulinic acid hydrochloride |
| CN103467326A (en) * | 2013-08-02 | 2013-12-25 | 苏州摩尔医药有限公司 | Synthetic method for 5-aminolevulinic acid hydrochloride |
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| CN108409561A (en) * | 2017-05-11 | 2018-08-17 | 上海本素医药科技有限公司 | A kind of preparation method of 5-aminoketoglutarate hydrochloride and intermediate |
| CN108440319A (en) * | 2018-04-26 | 2018-08-24 | 爱斯特（成都）生物制药股份有限公司 | A kind of new method preparing 5-ALA |
| CN111635464A (en) * | 2020-05-12 | 2020-09-08 | 上海易全化学有限公司 | Preparation method of 5-aminolevulinic acid dextran ester |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101891639A (en) * | 2009-05-20 | 2010-11-24 | 上海先导化学有限公司 | Method for preparing 5-aminolevulinic acid hydrochloride |
| CN102627573A (en) * | 2012-03-30 | 2012-08-08 | 山东大学 | Synthesis method for 5-aminolevulinic acid hydrochloride |
| CN103467326A (en) * | 2013-08-02 | 2013-12-25 | 苏州摩尔医药有限公司 | Synthetic method for 5-aminolevulinic acid hydrochloride |
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