CN116283604A - Preparation method of spermidine - Google Patents
Preparation method of spermidine Download PDFInfo
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- CN116283604A CN116283604A CN202211669862.4A CN202211669862A CN116283604A CN 116283604 A CN116283604 A CN 116283604A CN 202211669862 A CN202211669862 A CN 202211669862A CN 116283604 A CN116283604 A CN 116283604A
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- spermidine
- bromobutyl
- benzyl
- bromo
- hydrobromic acid
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- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 229940063673 spermidine Drugs 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- -1 2-((4-bromobutyl) amino) -2-oxoacetyl chloride Chemical compound 0.000 claims abstract description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 27
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 22
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims abstract description 18
- PZKCNXZSEAHUGH-UHFFFAOYSA-N 4-bromobutylazanium;bromide Chemical compound Br.NCCCCBr PZKCNXZSEAHUGH-UHFFFAOYSA-N 0.000 claims abstract description 13
- PQIYSSSTRHVOBW-UHFFFAOYSA-N 3-bromopropan-1-amine;hydron;bromide Chemical compound Br.NCCCBr PQIYSSSTRHVOBW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 239000007868 Raney catalyst Substances 0.000 claims abstract description 9
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229910000564 Raney nickel Inorganic materials 0.000 claims abstract description 9
- QYCNKZHRVLDNGO-UHFFFAOYSA-N 5-phenylpentane-1,4-diamine Chemical compound NCCCC(N)CC1=CC=CC=C1 QYCNKZHRVLDNGO-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 55
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 50
- 238000000034 method Methods 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 claims 2
- 229940063675 spermine Drugs 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 23
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000005406 washing Methods 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 238000005457 optimization Methods 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 230000001276 controlling effect Effects 0.000 description 7
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 6
- 238000007792 addition Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000004817 gas chromatography Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000012535 impurity Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 2
- 238000007259 addition reaction Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000004900 autophagic degradation Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000005305 organ development Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/84—Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D255/00—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00
- C07D255/02—Heterocyclic compounds containing rings having three nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D249/00 - C07D253/00 not condensed with other rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of spermidine, which comprises the steps of dissolving oxalyl chloride and alkali in a first solvent, slowly adding 4-bromo-1-butylamine hydrobromic acid, and reacting to obtain 2-((4-bromobutyl) amino) -2-oxoacetyl chloride; adding alkali into the prepared 2- ((4-bromobutyl) amino) -2-oxo acetyl chloride reaction solvent, slowly adding 3-bromo-1-propylamine hydrobromic acid to prepare N 1 - (4-bromobutyl) -N 2 - (3-bromopropyl) oxamide; will N 1 - (4-bromobutyl) -N 2 Adding the- (3-bromopropyl) oxamide, benzylamine and alkali into a second solvent, and reacting to obtain 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione; adding 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione into acid for hydrolysis to obtain N 1 - (3-aminopropyl) -N 1 -benzyl butane-1, 4-diamine; will N 1 - (3-aminopropyl) -N 1 Adding Raney nickel/methanol into the benzyl butane-1, 4-diamine, introducing hydrogen to react to obtain crude spermidine, and rectifying to obtain pure spermidine. The preparation method of the invention is easy to operate and safe, is easy for industrial scale production, and has high conversion rate of spermidine and high product purity.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of spermidine.
Background
Spermidine (spermidine) is a low molecular weight aliphatic carbide containing 3 amine groups and is one of the natural polyamines present in all organisms. As an important pharmaceutical synthetic raw material, it is widely used for the synthesis of pharmaceutical intermediates. Spermidine is involved in many biological processes in the organism, such as regulating physiological and pathological processes such as cell proliferation, cell senescence, organ development, immunity, and cancer. Recent studies have shown that spermidine has important regulatory effects on processes such as synaptic plasticity, oxidative stress and autophagy in the nervous system.
The existing synthesis method of spermidine mainly uses 1, 4-butanediamine and acrylonitrile as raw materials, and firstly carries out addition reaction, and then carries out cyanidation reduction on cyano to obtain spermidine. Although the synthesis method only needs two steps of reaction, the steps are short, the synthesis method has two defects that a large amount of excess 1, 4-butanediamine is difficult to remove, and the addition reaction of acrylonitrile and 1, 4-butanediamine has more impurities, has similar physicochemical properties to spermidine, is difficult to purify, and is not beneficial to industrial production and wider application fields.
Disclosure of Invention
The present invention is directed to a method for preparing spermidine, which solves the problems set forth in the background art.
In order to achieve the above purpose, the invention adopts the following technical scheme: a method for preparing spermidine, comprising the following steps:
s1) dissolving oxalyl chloride and alkali in a first solvent, slowly adding 4-bromo-1-butylamine hydrobromic acid, and reacting to obtain 2- ((4-bromobutyl) amino) -2-oxo acetyl chloride;
s2) adding alkali into the prepared 2- ((4-bromobutyl) amino) -2-oxo acetyl chloride reaction solvent, slowly adding 3-bromo-1-propylamine hydrobromic acid to prepare N 1 - (4-bromobutyl) -N 2 - (3-bromopropyl) oxamide;
s3) N is to 1 - (4-bromobutyl) -N 2 Adding the- (3-bromopropyl) oxamide, benzylamine and alkali into a second solvent, and reacting to obtain 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione;
s4) adding 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione into acid for hydrolysis to obtain N 1 - (3-aminopropyl) -N 1 -benzyl butane-1, 4-diamine;
s5) N is to 1 - (3-aminopropyl) -N 1 Adding Raney nickel/methanol into the benzyl butane-1, 4-diamine, introducing hydrogen to react to obtain crude spermidine, and rectifying to obtain pure spermidine.
As a further optimization, the molar ratio of oxalyl chloride in S1 to 4-bromo-1-butylamine hydrobromic acid is (1-1.2): 1.
As a further optimization, the base in S1 is one or more of triethylamine, trimethylamine or N, N-diisopropylethylamine, preferably triethylamine, and the molar ratio of the triethylamine to the 4-bromo-1-butylamine hydrobromic acid is (2-2.5): 1, optionally 2:1.
As a further refinement, the first solvent in S1 is one or more of dichloromethane, dichloroethane, tetrahydrofuran or DMF, preferably dichloromethane, in a weight ratio to 4-bromo-1-butylamine hydrobromic acid of (1-10): 1, optionally 10:1.
As a further optimization, the base in S2 is one or more of triethylamine, trimethylamine or N, N-diisopropylethylamine, preferably triethylamine, and the molar ratio of the triethylamine to the 3-bromo-1-propylamine hydrobromic acid is (2-2.5): 1, optionally 2:1.
As a further optimization, the molar ratio of 3-bromo-1-propylamine hydrobromic acid to oxalyl chloride in S2 is (1-1.2): 1.
As a further optimization, benzylamine in S3 and N 1 - (4-bromobutyl) -N 2 The molar ratio of the- (3-bromopropyl) oxamide is (0.9-1): 1, optionally 1:1.
As a further optimization, the alkali in S3 is one or more of triethylamine, potassium carbonate or sodium carbonate, preferably potassium carbonate or sodium carbonate, which is combined with N 1 - (4-bromobutyl) -N 2 The molar ratio of the- (3-bromopropyl) oxamide is(2-3): 1, optionally 1.2:1.
As a further optimization, the second solvent in S3 is one or more of dichloromethane, dichloroethane, tetrahydrofuran, dioxane or toluene, preferably dichloromethane, which is mixed with N 1 - (4-bromobutyl) -N 2 The weight ratio of the- (3-bromopropyl) oxamide is (5-10): 1, and the optional weight ratio is 10:1.
As a further refinement, the acid in S4 is a 10% aqueous solution of hydrochloric acid or sulfuric acid, the mass ratio of which to 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione is (8-10): 1, preferably 10:1.
As a further optimization, raney Nickel in S5 is mixed with N 1 - (3-aminopropyl) -N 1 The mass ratio of the benzylbutane-1, 4-diamine is (0.1-0.3): 1, preferably 0.2:1.
As a further optimization, the methanol in S5 is mixed with N 1 - (3-aminopropyl) -N 1 The mass ratio of the benzylbutane-1, 4-diamine is (6-10): 1, preferably 6:1.
The preparation flow of the invention is as follows:
compared with the prior art, the invention has the beneficial effects that:
1. the preparation method is easy to operate, safe to operate and easy for industrial mass production;
2. the raw materials used in the invention have low cost, environmental protection and no pollution;
3. the conversion rate of the spermidine prepared by the method is high, the product and impurities are easy to separate, and the product purity is high.
Detailed Description
The following are specific examples of the present invention, and the technical solutions of the present invention are further described, but the present invention is not limited to these examples.
Example 1
A method for preparing spermidine, comprising the following steps:
s1) dissolving 139.7g of oxalyl chloride and 202.4g of triethylamine in 2.3kg of dichloromethane, controlling the temperature to be 0 ℃, slowly adding 233g of 4-bromo-1-butylamine hydrobromic acid, and after the reaction is finished, carrying out heat preservation for 2 hours, and detecting the end of the reaction;
s2) adding 202g of triethylamine into the 2- ((4-bromobutyl) amino) -2-oxoacetyl chloride reaction solvent prepared in S1, controlling the temperature to be 0 ℃, slowly adding 265g of 3-bromo-1-propylamine hydrobromic acid, heating to 25 ℃ after the addition, reacting for 2 hours, detecting the end of the reaction, filtering to remove triethylamine salt, adding water, layering, washing once with 10% citric acid water, layering, washing once, drying and evaporating to obtain 320g N 1 - (4-bromobutyl) -N 2 - (3-bromopropyl) oxamide;
s3) will be 320g N 1 - (4-bromobutyl) -N 2 - (3-bromopropyl) oxamide, 99.6g benzylamine, 154g potassium carbonate and 3.2kg dichloromethane, reflux-reacting for 8 hours, detecting the end of the reaction, filtering the salt, adding water into the filtrate for washing, drying and concentrating to obtain 242g 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione;
s4) 242g of 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione are added to 2.4kg
Reflux-reacting in 10% hydrochloric acid for 10 hr, refluxing with 10g active carbon for 2 hr, filtering, adjusting pH to 9 with sodium hydroxide, extracting with DCM, washing with water, drying, and concentrating to obtain 157g N 1 - (3-aminopropyl) -N 1 -benzyl butane-1, 4-diamine;
s5) charging 157g N into a 2L autoclave 1 - (3-aminopropyl) -N 1 Benzyl butane-1, 4-diamine, 30g Raney nickel and 1kg methanol are reacted for 24 hours at 60 ℃ under the pressure of 2.0MPa by hydrogen, the reaction liquid is filtered, concentrated and dried to obtain crude product, and 81.3g colorless transparent spermidine is obtained by rectification.
The purity was 99.9% by gas chromatography.
Example 2
A method for preparing spermidine, comprising the following steps:
s1) dissolving 139.7g of oxalyl chloride and 202.4g of triethylamine in 2.3kg of dichloromethane, controlling the temperature to be 0 ℃, slowly adding 233g of 4-bromo-1-butylamine hydrobromic acid, and after the reaction is finished, carrying out heat preservation for 2 hours, and detecting the end of the reaction;
s2) 202g of Tri-in the 2- ((4-bromobutyl) amino) -2-oxoacetyl chloride reaction solvent prepared in S1Slowly adding 265g of 3-bromo-1-propylamine hydrobromic acid at the temperature of 0 ℃, heating to 25 ℃ after the addition, reacting for 2 hours, detecting the end of the reaction, filtering to remove triethylamine salt, adding water, layering, washing with 10% citric acid water for one time, layering, washing with water for one time, drying and evaporating to obtain 325g N 1 - (4-bromobutyl) -N 2 - (3-bromopropyl) oxamide;
s3) will be 325g N 1 - (4-bromobutyl) -N 2 - (3-bromopropyl) oxamide, 101.1g benzylamine, 156.4g potassium carbonate and 3.2kg dichloromethane, refluxing for 8 hours, detecting the end of the reaction, filtering the salt, washing the filtrate with water, drying, and concentrating to obtain 247g 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione;
s4) adding 247g of 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione into 2.4kg of 10% sulfuric acid, carrying out reflux reaction for 10h, adding 10g of active carbon, refluxing for 2h, filtering, adding sodium hydroxide to adjust pH to 9, DCM extracting, washing with water, drying, concentrating to obtain 161.6g N 1 - (3-aminopropyl) -N 1 -benzyl butane-1, 4-diamine;
s5) adding 161.6. 161.6g N to a 2L autoclave 1 - (3-aminopropyl) -N 1 Benzyl butane-1, 4-diamine, 30g Raney nickel and 1kg methanol are reacted for 24 hours at 60 ℃ under the pressure of 2.0MPa by hydrogen, the reaction liquid is filtered, concentrated and dried to obtain crude product, and 85g colorless transparent spermidine is obtained by rectification.
The purity was 99.8% by gas chromatography.
Example 3
A method for preparing spermidine, comprising the following steps:
s1) dissolving 139.7g of oxalyl chloride and 202.4g of triethylamine in 2.3kg of dichloromethane, controlling the temperature to be 0 ℃, slowly adding 233g of 4-bromo-1-butylamine hydrobromic acid, and after the reaction is finished, carrying out heat preservation for 2 hours, and detecting the end of the reaction;
s2) adding 202g of triethylamine into the 2- ((4-bromobutyl) amino) -2-oxoacetyl chloride reaction solvent prepared in S1, controlling the temperature to be 0 ℃, slowly adding 265g of 3-bromo-1-propylamine hydrobromic acid, heating to 25 ℃ after the addition, reacting for 2 hours, detecting the end of the reaction, filtering to remove triethylamine salt, adding water, layering, washing once with 10% citric acid water, layering, washing once, drying and evaporating to obtain 313g N 1 - (4-bromobutyl))-N 2 - (3-bromopropyl) oxamide;
s3) will 313g N 1 - (4-bromobutyl) -N 2 - (3-bromopropyl) oxamide, 97.4g benzylamine, 115.6g sodium carbonate and 3.2kg dichloromethane, refluxing for 8 hours, detecting the end of the reaction, filtering the salt, washing the filtrate with water, drying, concentrating to obtain 237.5g 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione;
s4) adding 237.5g of 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione into 2.4kg of 10% hydrochloric acid, carrying out reflux reaction for 10h, adding 10g of active carbon, refluxing for 2h, filtering, adding sodium hydroxide to adjust pH to 9, DCM extracting, washing with water, drying, concentrating to obtain 152.4g N 1 - (3-aminopropyl) -N 1 -benzyl butane-1, 4-diamine;
s5) adding 152.4. 152.4g N to a 2L autoclave 1 - (3-aminopropyl) -N 1 Benzyl butane-1, 4-diamine, 30g Raney nickel and 1kg methanol are reacted for 24 hours at 60 ℃ under the pressure of 2.0MPa by hydrogen, the reaction liquid is filtered, concentrated and dried to obtain crude product, and 79.3g colorless transparent spermidine is obtained by rectification.
The purity by gas chromatography was 99.9% GC.
Example 4
A method for preparing spermidine, comprising the following steps:
s1) dissolving 139.7g of oxalyl chloride and 202.4g of triethylamine in 2.3kg of dichloromethane, controlling the temperature to be 0 ℃, slowly adding 233g of 4-bromo-1-butylamine hydrobromic acid, and after the reaction is finished, carrying out heat preservation for 2 hours, and detecting the end of the reaction;
s2) adding 202g of triethylamine into the 2- ((4-bromobutyl) amino) -2-oxoacetyl chloride reaction solvent prepared in S1, controlling the temperature to be 0 ℃, slowly adding 265g of 3-bromo-1-propylamine hydrobromic acid, heating to 25 ℃ after the addition, reacting for 2 hours, detecting the end of the reaction, filtering to remove triethylamine salt, adding water, layering, washing once with 10% citric acid water, layering, washing once, drying and evaporating to obtain 317g N 1 - (4-bromobutyl) -N 2 - (3-bromopropyl) oxamide;
s3) will 317g N 1 - (4-bromobutyl) -N 2 - (3-bromopropyl) oxamide, 98.6g benzylamine, 117.1g sodium carbonate and 3.2kg dichloromethane, reflux-reacting for 8 hours, detecting the end of the reaction, filtering the salt, washing the filtrate with waterDrying and concentrating to obtain 241.3g of 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione;
s4) adding 241.3g of 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione into 2.4kg of 10% hydrochloric acid, carrying out reflux reaction for 10h, adding 10g of active carbon, refluxing for 2h, filtering, adding sodium hydroxide to adjust pH to 9, DCM extracting, washing with water, drying, concentrating to obtain 154.8g N 1 - (3-aminopropyl) -N 1 -benzyl butane-1, 4-diamine;
s5) into a 2L autoclave was charged 154.8. 154.8g N 1 - (3-aminopropyl) -N 1 Benzyl butane-1, 4-diamine, 30g Raney nickel and 1kg methanol are reacted for 24 hours at 60 ℃ under the pressure of 2.0MPa by hydrogen, the reaction liquid is filtered, concentrated and dried to obtain crude product, and 81.5g colorless transparent spermidine is obtained by rectification.
The purity by gas chromatography was 99.9% GC.
The preparation method has the advantages of simple process, easy operation, environmental protection, no pollution, low cost, safe operation, easy industrial scale production, high conversion rate, easy separation of products and impurities and high product purity.
The specific embodiments described herein are offered by way of example only to illustrate the spirit of the invention. Those skilled in the art may make various modifications or additions to the described embodiments or substitutions thereof without departing from the spirit of the invention or exceeding the scope of the invention as defined in the accompanying claims.
Claims (10)
1. The preparation method of spermidine is characterized by comprising the following steps:
s1) dissolving oxalyl chloride and alkali in a first solvent, slowly adding 4-bromo-1-butylamine hydrobromic acid, and reacting to obtain 2- ((4-bromobutyl) amino) -2-oxo acetyl chloride;
s2) adding alkali into the prepared 2- ((4-bromobutyl) amino) -2-oxo acetyl chloride reaction solvent, slowly adding 3-bromo-1-propylamine hydrobromic acid to prepare N 1 - (4-bromobutyl) -N 2 - (3-bromopropyl) oxamide;
s3) N is to 1 - (4-bromobutyl) -N 2 - (3-bromopropyl) oxamide, benzylamine and base are added to a second solvent,reacting to obtain 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione;
s4) adding 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione into acid for hydrolysis to obtain N 1 - (3-aminopropyl) -N 1 -benzyl butane-1, 4-diamine;
s5) N is to 1 - (3-aminopropyl) -N 1 Adding Raney nickel/methanol into the benzyl butane-1, 4-diamine, introducing hydrogen to react to obtain crude spermidine, and rectifying to obtain pure spermidine.
2. The process for producing spermidine according to claim 1, wherein the molar ratio of oxalyl chloride to 4-bromo-1-butylamine hydrobromic acid in S1 is (1-1.2): 1.
3. The process for producing spermidine according to claim 1, wherein the base in S1 is one or more of triethylamine, trimethylamine or N, N-diisopropylethylamine in a molar ratio of (2-2.5) to 4-bromo-1-butylamine hydrobromic acid of 1; the first solvent in S1 is one or more of dichloromethane, dichloroethane, tetrahydrofuran or DMF, and the weight ratio of the first solvent to 4-bromo-1-butylamine hydrobromic acid is (1-10): 1.
4. The process for producing spermidine according to claim 1, wherein the base in S2 is one or more of triethylamine, trimethylamine and N, N-diisopropylethylamine, and the molar ratio of the base to 3-bromo-1-propylamine hydrobromic acid is (2-2.5): 1.
5. The process for producing spermidine according to claim 1, wherein the molar ratio of 3-bromo-1-propylamine hydrobromic acid to oxalyl chloride in S2 is (1-1.2): 1.
6. The process for producing spermidine according to claim 1, wherein the benzylamine in S3 is mixed with N 1 - (4-bromobutyl) -N 2 The molar ratio of the- (3-bromopropyl) oxamide is (0.9-1): 1.
7. A sub-assembly according to claim 1A preparation method of spermine is characterized in that the alkali in S3 is one or more of triethylamine, potassium carbonate or sodium carbonate, and the alkali and N are mixed 1 - (4-bromobutyl) -N 2 The molar ratio of the- (3-bromopropyl) oxamide is (2-3): 1.
8. The process for producing spermidine according to claim 1, wherein the second solvent in S3 is one or more of dichloromethane, dichloroethane, tetrahydrofuran, dioxane or toluene, which is mixed with N 1 - (4-bromobutyl) -N 2 The weight ratio of the- (3-bromopropyl) oxamide is (5-10): 1.
9. The process for producing spermidine according to claim 1, wherein the acid in S4 is a 10% aqueous solution of hydrochloric acid or sulfuric acid, and the mass ratio of the acid to 8-benzyl-1, 4, 8-triazacyclododecane-2, 3-dione is (8-10): 1.
10. The process for producing spermidine according to claim 1, wherein the Raney nickel in S5 is mixed with N 1 - (3-aminopropyl) -N 1 The mass ratio of the (0.1-0.3) benzyl butane-1, 4-diamine is 1; methanol and N 1 - (3-aminopropyl) -N 1 The mass ratio of the (6-10) benzyl butane-1, 4-diamine is 1.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4134918A (en) * | 1977-09-06 | 1979-01-16 | Merrell Toraude Et Compagnie | Alpha-halomethyl derivatives of amines |
| US4505861A (en) * | 1982-07-23 | 1985-03-19 | University Of Florida | Methods and intermediates for the preparation of spermidine, homospermidine and norspermidine |
| WO1994019366A1 (en) * | 1993-02-26 | 1994-09-01 | Magainin Pharmaceuticals Inc. | Chemical synthesis of squalamine |
| FR2723736A1 (en) * | 1994-08-16 | 1996-02-23 | Fournier Sca Lab | Spermidine homologues prepn. |
| US20030105335A1 (en) * | 2000-03-03 | 2003-06-05 | Stefan Hildrand | Method for producing beta-alaninamides |
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2022
- 2022-12-25 CN CN202211669862.4A patent/CN116283604A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4134918A (en) * | 1977-09-06 | 1979-01-16 | Merrell Toraude Et Compagnie | Alpha-halomethyl derivatives of amines |
| US4505861A (en) * | 1982-07-23 | 1985-03-19 | University Of Florida | Methods and intermediates for the preparation of spermidine, homospermidine and norspermidine |
| WO1994019366A1 (en) * | 1993-02-26 | 1994-09-01 | Magainin Pharmaceuticals Inc. | Chemical synthesis of squalamine |
| FR2723736A1 (en) * | 1994-08-16 | 1996-02-23 | Fournier Sca Lab | Spermidine homologues prepn. |
| US20030105335A1 (en) * | 2000-03-03 | 2003-06-05 | Stefan Hildrand | Method for producing beta-alaninamides |
Non-Patent Citations (1)
| Title |
|---|
| PAPADOPOULOU MV: "Synthesis of a novel nitroimidazole-spermidine derivative as a tumor-targeted hypoxia-selective cytotoxin", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 14, no. 6, 22 March 2004 (2004-03-22), XP002554045, DOI: 10.1016/j.bmcl.2003.12.100 * |
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