CN116162029B - Preparation method of spermine - Google Patents
Preparation method of spermine Download PDFInfo
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- CN116162029B CN116162029B CN202211596304.XA CN202211596304A CN116162029B CN 116162029 B CN116162029 B CN 116162029B CN 202211596304 A CN202211596304 A CN 202211596304A CN 116162029 B CN116162029 B CN 116162029B
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- hydrazine
- chloropropyl
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- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 229940063675 spermine Drugs 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 28
- -1 1,2-bis(3-chloropropyl)hydrazine Chemical compound 0.000 claims abstract description 24
- FFDNRFMIOVQZMT-UHFFFAOYSA-N 3-chloropropanal Chemical compound ClCCC=O FFDNRFMIOVQZMT-UHFFFAOYSA-N 0.000 claims abstract description 22
- 241000219198 Brassica Species 0.000 claims abstract description 17
- 235000003351 Brassica cretica Nutrition 0.000 claims abstract description 17
- 235000003343 Brassica rupestris Nutrition 0.000 claims abstract description 17
- 235000010460 mustard Nutrition 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- LAMUXTNQCICZQX-UHFFFAOYSA-N 3-chloropropan-1-ol Chemical compound OCCCCl LAMUXTNQCICZQX-UHFFFAOYSA-N 0.000 claims abstract description 11
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 claims abstract description 9
- HTFFABIIOAKIBH-UHFFFAOYSA-N diazinane Chemical compound C1CCNNC1 HTFFABIIOAKIBH-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000007800 oxidant agent Substances 0.000 claims abstract description 7
- 230000001590 oxidative effect Effects 0.000 claims abstract description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical group O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 5
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- DPOPAJRDYZGTIR-UHFFFAOYSA-N Tetrazine Chemical compound C1=CN=NN=N1 DPOPAJRDYZGTIR-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 45
- 239000000706 filtrate Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 235000019441 ethanol Nutrition 0.000 description 10
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000012295 chemical reaction liquid Substances 0.000 description 9
- 238000005457 optimization Methods 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 7
- 238000007792 addition Methods 0.000 description 6
- 239000005700 Putrescine Substances 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910017053 inorganic salt Inorganic materials 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 238000007711 solidification Methods 0.000 description 4
- 230000008023 solidification Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 229920000768 polyamine Polymers 0.000 description 2
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- CRBHXDCYXIISFC-UHFFFAOYSA-N 2-(Trimethylammonio)ethanolate Chemical compound C[N+](C)(C)CC[O-] CRBHXDCYXIISFC-UHFFFAOYSA-N 0.000 description 1
- NIDWUZTTXGJFNN-UHFFFAOYSA-N 3-bromopropoxybenzene Chemical compound BrCCCOC1=CC=CC=C1 NIDWUZTTXGJFNN-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- MEFKEPWMEQBLKI-AIRLBKTGSA-N S-adenosyl-L-methioninate Chemical compound O[C@@H]1[C@H](O)[C@@H](C[S+](CC[C@H](N)C([O-])=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 MEFKEPWMEQBLKI-AIRLBKTGSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229960001570 ademetionine Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QVYARBLCAHCSFJ-UHFFFAOYSA-N butane-1,1-diamine Chemical compound CCCC(N)N QVYARBLCAHCSFJ-UHFFFAOYSA-N 0.000 description 1
- 239000012930 cell culture fluid Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000005202 decontamination Methods 0.000 description 1
- 230000003588 decontaminative effect Effects 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003987 organophosphate pesticide Substances 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 229940063673 spermidine Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 229940034610 toothpaste Drugs 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
Classifications
-
- 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
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/16—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of hydrazones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
- C07C45/298—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with manganese derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种精胺的制备方法，包括如下步骤：S1)将3‑氯丙醇和氧化剂加入第一溶剂中，反应制得3‑氯丙醛；S2)将3‑氯丙醛溶于第二溶剂中，加入盐酸肼，缩合制得1,2‑双(3‑氯丙基)肼；S3)将1,2‑双(3‑氯丙基)肼溶于第三溶剂，加入第一催化剂，并加入六氢哒嗪，反应得到1,2,7,8,10,11,12,13‑八氢吡啶并[1,2‑a][1,2,6,7]四氮芥；S4)将1,2,7,8,10,11,12,13‑八氢吡啶并[1,2‑a][1,2,6,7]四氮芥溶于第四溶剂中，并加入第二催化剂，加氢反应制得精胺。本发明制备工艺更加简单，且易操作，环保无污染，成本低廉，操作安全，易于工业规模化生产，转化率高，产品质量好。The invention discloses a method for preparing spermine, comprising the following steps: S1) adding 3-chloropropanol and an oxidant into a first solvent, reacting to obtain 3-chloropropanal; S2) dissolving 3-chloropropanal into a second solvent, adding hydrazine hydrochloride, and condensing to obtain 1,2-bis(3-chloropropyl)hydrazine; S3) dissolving 1,2-bis(3-chloropropyl)hydrazine into a third solvent, adding a first catalyst, and adding hexahydropyridazine, reacting to obtain 1,2,7,8,10,11,12,13-octahydropyrido[1,2-a][1,2,6,7]tetrazolyl mustard; S4) dissolving 1,2,7,8,10,11,12,13-octahydropyrido[1,2-a][1,2,6,7]tetrazolyl mustard into a fourth solvent, adding a second catalyst, and performing a hydrogenation reaction to obtain spermine. The preparation process of the invention is simpler, easy to operate, environmentally friendly and pollution-free, low in cost, safe to operate, easy to industrially mass produce, with high conversion rate and good product quality.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of spermine.
Background
Spermine is a polyamine substance containing two amino groups and two imino groups, is produced in an organism by putrescine (butanediamine) and S-adenosyl methionine through catalysis of various enzymes, and is an important substance for promoting cell proliferation when the spermine and the spermidine are both in bacteria and most animal cells. Under acidic condition, it presents the characteristic of multi-cation polyamine, and can combine with DNA in virus and bacteria, make DNA molecule have greater stability and flexibility, have antiviral effect, it is one of necessary components in cell culture fluid, can also be regarded as organophosphorus pesticide intermediate, it is typical anionic surfactant at the same time, it has good infiltration, emulsifies, foam and decontamination ability, it is applied to industry such as chemical industry, pesticide, fiber, electrolysis, mineral dressing extensively, especially suitable for making of cosmetics, toothpaste, shampoo, etc., suitable for washing wool and silk in the textile industry. Spermine has high biological activity as a naturally occurring substance, can be used as a direct free radical scavenger, can protect DNA from being attacked by free radicals, inhibit DNA damage induced by ROS, and has wider application in life metabolism research.
Research work has increasingly demanded spermine, because spermine content in organisms is low, each component is difficult to separate, spermine cannot be directly extracted from biological fluid generally, and the step of chemically synthesizing spermine is simple and can be industrially produced, so that the demands of spermine must be met through chemical synthesis. The conventional synthesis method comprises the following two steps: rosenheim finds a first synthesis method of spermine, wherein the synthesis route is that phenyl bromopropyl ether and putrescine are alkylated to generate an ether amine compound, and ammonia water is used for ammonolysis to generate spermine.
The method has the advantages of poor reaction selectivity, serious polyalkylation phenomenon and low yield. Meanwhile, the raw materials are expensive and are difficult to produce in large scale.
Raymond et al used putrescine as raw materials, carried out Machel addition with acrylonitrile and putrescine, the product was hydrogenated under the catalysis of Raney nickel with 95% ethanol solution of sodium hydroxide at room temperature and 2.7 atmospheres to obtain spermine, and the total yield of putrescine was 38%.
The reaction condition of the route is mild, and the yield is higher. However, the hydrogenation reduction adopts sodium hydroxide with higher concentration to inhibit the generation of secondary amine, and the reaction is required to be carried out at low temperature in order to avoid the hydrolysis of cyano groups in alkaline, so that the reaction time is long, the raw materials are expensive, and the production cost is high.
Disclosure of Invention
The present invention is directed to a method for preparing spermine, 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 preparation method of spermine comprises the following steps:
s1) adding 3-chloropropanol and an oxidant into a first solvent, and reacting to obtain 3-chloropropionaldehyde;
S2) dissolving 3-chloropropionaldehyde in a second solvent, adding hydrazine hydrochloride, and condensing to obtain 1, 2-bis (3-chloropropyl) hydrazine;
S3) dissolving 1, 2-bis (3-chloropropyl) hydrazine in a third solvent, adding a first catalyst, adding hexahydropyridazine, and reacting to obtain 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard;
S4) dissolving 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard in a fourth solvent, adding a second catalyst, and carrying out hydrogenation reaction to obtain spermine.
As a further optimization, the oxidant in S1 is one or more of manganese dioxide, a Kolin reagent, PDC and DMP, and the molar ratio of the oxidant to 3-chloropropanol is (1-5): 1.
As a further optimization, the first solvent in S1 is one or more of dichloromethane, water, DMSO, tert-butanol and DMF, and the weight ratio of the first solvent to 3-chloropropanol is (1-10): 1.
As a further optimization, the second solvent in S2 is one or more of methanol, ethanol, isopropanol, toluene and DMF, and the weight ratio of the second solvent to 3-chloropropionaldehyde is (1-10): 1.
As a further optimization, the molar ratio of hydrazine hydrochloride to 3-chloropropionaldehyde in the S2 is (0.2-1): 1.
As a further optimization, the third solvent in S3 is one or more of methanol, ethanol, ethyl acetate, water, DMF and toluene, and the weight ratio of the third solvent to 1, 2-bis (3-chloropropyl) hydrazine is (1-20): 1.
As a further optimization, the first catalyst in S3 is sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide or sodium methoxide, and the molar ratio of the first catalyst to 1, 2-bis (3-chloropropyl) hydrazine is (0.5-10): 1.
As a further optimization, the molar ratio of the hexahydropyridazine in S3 to the 1, 2-bis (3-chloropropyl) hydrazine is (0.5-1.5): 1.
As a further optimization, the fourth solvent in S4 is one or more of methanol, ethanol and ethyl acetate, and the weight ratio of the fourth solvent to 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard is (1-20): 1.
As further optimization, the second catalyst in S4 is one or more of 5% palladium carbon, 10% palladium carbon, palladium hydroxide, palladium chloride and the like, and the weight ratio of the second catalyst to 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard is (0.05-1): 1.
In summary, the preparation process of the spermine of the invention is as follows:
compared with the prior art, the invention has the beneficial effects that:
1. The preparation process is simpler, is easy to operate, is environment-friendly and pollution-free, and is low in cost and safe to operate;
2. The invention is easy for industrial mass production, high in conversion rate and good in product quality.
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
S1) oxidation reaction: 950g of dichloromethane, 94.54g (1 mol) of 3-chloropropanol and 430g (5 mol) of manganese dioxide are added into a 2L three-necked flask, the temperature is kept at 30 ℃, the reaction is carried out for 24 hours, the reaction is detected, the reaction liquid is filtered, a small amount of dichloromethane is used for washing a filter cake, and the filtrate is concentrated to be dry, so that 73.6g (80%) of 3-chloropropanal is obtained;
S2) condensation reaction: adding 73.6g of 3-chloropropionaldehyde into 400g of ethanol, dissolving, adding 24.5g of hydrazine hydrochloride into the reaction solution, heating and refluxing after the addition, reacting for 3 hours, cooling to 20 ℃ after the reaction is finished, adjusting the pH to 8 by using a saturated sodium carbonate aqueous solution, concentrating the reaction solution in vacuum until the 3-chloropropionaldehyde is not detected, adding absolute ethanol again, filtering to remove inorganic salt, concentrating the filtrate until the filtrate is dried to obtain 64.8g of 1, 2-bis (3-chloropropyl) hydrazine;
s3) substitution reaction: 64.8g of 1, 2-bis (3-chloropropyl) hydrazine, 350g of ethanol, 76g of sodium carbonate and 27.7g of hexahydropyridazine are added into a bottle, the reaction is completed after the heating reflux reaction is carried out for 5 hours, the reaction liquid is filtered, and the filtrate is concentrated to dryness to obtain 70g 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard;
S4) reduction reaction: 70g 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard, 420g of methanol, 14g of 10% Pt/C and 2.0Mpa at 100 ℃ are added into an autoclave for reaction for 24 hours, the reaction is finished, the reaction solution is filtered, concentrated to dryness, vacuum rectification is carried out to obtain 58g of colorless transparent liquid, and the colorless transparent liquid is placed at room temperature for solidification crystallization.
The overall yield of this example was 57.3%.
Example 2
S1) oxidation reaction: 950g of dichloromethane, 94.54g (1 mol) of 3-chloropropanol and 400g (5 mol) of manganese dioxide are added into a 2L three-necked flask, the temperature is kept at 30 ℃, the reaction is carried out for 24 hours, the reaction is detected, a reaction liquid is filtered, a small amount of dichloromethane is used for washing a filter cake, and the filtrate is concentrated to be dry, so that 67.16g (72.6%) of 3-chloropropionaldehyde is obtained;
S2) condensation reaction: adding 67.16g of 3-chloropropionaldehyde into 400g of methanol, dissolving, adding 22.38g of hydrazine hydrochloride into the reaction solution, heating and refluxing after the addition, reacting for 3 hours, cooling to 20 ℃ after the reaction is finished, regulating the pH value to 8 by using a saturated sodium carbonate aqueous solution, concentrating the reaction solution in vacuum until the 3-chloropropionaldehyde is not detected, adding methanol again, filtering to remove inorganic salt, concentrating the filtrate until the filtrate is dried to obtain 60.2g of 1, 2-bis (3-chloropropyl) hydrazine;
S3) substitution reaction: 60.2g of 1, 2-bis (3-chloropropyl) hydrazine, 350g of ethyl acetate, 100g of potassium carbonate and 25.77g of hexahydropyridazine are added into a bottle, the reaction is completed after the heating reflux reaction is completed for 5 hours, the reaction liquid is filtered, and the filtrate is concentrated and dried to obtain 65.7g 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard;
S4) reduction reaction: 65.7g 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard and 420g ethanol, 13.2g of 10% Pt/C and 2.0Mpa and 100 ℃ are added into an autoclave for reaction for 24 hours, the reaction is finished, the reaction solution is filtered, concentrated to dryness, and vacuum rectification is carried out to obtain 53.2g of colorless transparent liquid, and the colorless transparent liquid is placed at room temperature for solidification and crystallization.
The overall yield of this example was 52.58%.
Example 3
S1) oxidation reaction: 950g of dichloromethane, 94.54g (1 mol) of 3-chloropropanol and 400g (5 mol) of manganese dioxide are added into a 2L three-necked flask, the temperature is kept at 30 ℃, the reaction is carried out for 36 hours, the reaction is detected, the reaction liquid is filtered, a small amount of dichloromethane is used for washing a filter cake, and the filtrate is concentrated to be dried, so as to obtain 82.6g (89 percent) of 3-chloropropanal;
S2) condensation reaction: adding 82.6g of 3-chloropropionaldehyde into 400g of toluene, dissolving, adding 24.46g of hydrazine hydrochloride into the reaction solution, heating and refluxing after the addition, reacting for 4 hours, cooling to 20 ℃ after the reaction is finished, regulating the pH value to 8 by using a saturated sodium carbonate aqueous solution, concentrating the reaction solution in vacuum until the 3-chloropropionaldehyde is not detected, adding absolute ethyl alcohol again, filtering to remove inorganic salt, concentrating the filtrate until the filtrate is dried to obtain 64.65g of 1, 2-bis (3-chloropropyl) hydrazine;
S3) substitution reaction: 64.65g of 1, 2-bis (3-chloropropyl) hydrazine, 350g of ethanol, 100g of potassium carbonate and 27.68g of hexahydropyridazine are added into a bottle, the reaction is completed after the heating reflux reaction is completed for 5 hours, the reaction liquid is filtered, and the filtrate is concentrated and dried to obtain 68.9g 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard;
s4) reduction reaction: 68.9g 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard, 420g of methanol, 13.2g of 10% Pt/C,2.0Mpa and 100 ℃ are added into an autoclave for reaction for 24 hours, the reaction is finished, the reaction solution is filtered, concentrated to dryness, and vacuum rectification is carried out to obtain 57.4g of colorless transparent liquid, and the liquid is placed at room temperature for solidification and crystallization.
The overall yield of this example was 56.7%.
Example 4
S1) oxidation reaction: 950g of dichloromethane, 94.54g (1 mol) of 3-chloropropanol and 400g (5 mol) of manganese dioxide are added into a 2L three-necked flask, the temperature is kept at 30 ℃, the reaction is carried out for 36 hours, the reaction is detected, the reaction liquid is filtered, a small amount of dichloromethane is used for washing a filter cake, and the filtrate is concentrated to be dry, thus obtaining 84g (90.8%) of 3-chloropropanal;
S2) condensation reaction: adding 84g of 3-chloropropionaldehyde into 400g of ethanol, dissolving, adding 27.99g of hydrazine hydrochloride into the reaction solution, heating up and refluxing after the addition, reacting for 4 hours, cooling to 20 ℃ after the reaction is finished, regulating the pH value to 8 by using a saturated sodium carbonate aqueous solution, concentrating the reaction solution in vacuum until the 3-chloropropionaldehyde is not detected, adding absolute ethanol again, filtering to remove inorganic salt, concentrating the filtrate to dryness, and obtaining 74.5g of 1, 2-bis (3-chloropropyl) hydrazine;
S3) substitution reaction: 74.5g of 1, 2-bis (3-chloropropyl) hydrazine, 360g of ethanol, 90g of sodium carbonate and 31.9g of hexahydropyridazine are added into a bottle, the reaction is completed after the temperature is raised, the reflux reaction is carried out for 5 hours, the reaction liquid is filtered, and the filtrate is concentrated to dryness to obtain 79.3g 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard.
S4) reduction reaction: 79.3g 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard, 420g of methanol, 16g of 10% Pt/C and 2.0Mpa at 100 ℃ are added into an autoclave for reaction for 24 hours, the reaction liquid is filtered after the reaction is finished, concentrated to dryness, vacuum rectification is carried out to obtain 63g of colorless transparent liquid, and the colorless transparent liquid is placed at room temperature for solidification crystallization.
The overall yield of this example was 62.3%.
In summary, the preparation method has the advantages of simple process, easy operation, environmental protection, no pollution, low cost, safe operation, easy industrial mass production, high conversion rate and good product quality.
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 spermine is characterized by comprising the following steps:
s1) adding 3-chloropropanol and an oxidant into a first solvent, wherein the oxidant is manganese dioxide, and reacting to prepare 3-chloropropionaldehyde;
S2) dissolving 3-chloropropionaldehyde in a second solvent, adding hydrazine hydrochloride, and condensing to obtain 1, 2-bis (3-chloropropyl) hydrazine;
S3) dissolving 1, 2-bis (3-chloropropyl) hydrazine in a third solvent, adding a first catalyst which is sodium carbonate or potassium carbonate, adding hexahydropyridazine, and reacting to obtain 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard;
s4) dissolving 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard in a fourth solvent, and adding a second catalyst, wherein the second catalyst is 10% Pt/C, and carrying out hydrogenation reaction to obtain spermine.
2. The process for producing spermine according to claim 1, wherein the molar ratio of the oxidizing agent to 3-chloropropanol in S1 is (1-5): 1.
3. The method for preparing spermine according to claim 1, wherein the first solvent in S1 is one or more of dichloromethane, water, DMSO, tert-butanol and DMF, and the weight ratio of the first solvent to 3-chloropropanol is (1-10): 1.
4. The process for producing spermine according to claim 1, wherein the second solvent in S2 is one or more of methanol, ethanol, isopropanol, toluene and DMF, and the weight ratio of the second solvent to 3-chloropropionaldehyde is (1-10): 1.
5. The process for producing spermine according to claim 1, wherein the molar ratio of hydrazine hydrochloride to 3-chloropropionaldehyde in S2 is (0.2-1): 1.
6. The process for producing spermine according to claim 1, wherein the third solvent in S3 is one or more of methanol, ethanol, ethyl acetate, water, DMF and toluene, and the weight ratio of the third solvent to 1, 2-bis (3-chloropropyl) hydrazine is (1-20): 1.
7. The process for producing spermine according to claim 1, wherein the molar ratio of the first catalyst in S3 to 1, 2-bis (3-chloropropyl) hydrazine is (0.5-10): 1.
8. The process for producing spermine according to claim 1, wherein the molar ratio of hexahydropyridazine to 1, 2-bis (3-chloropropyl) hydrazine in S3 is (0.5-1.5): 1.
9. The process for producing spermine according to claim 1, wherein the fourth solvent in S4 is one or more of methanol, ethanol and ethyl acetate, and the weight ratio of the fourth solvent to 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetranitrogen mustard is (1-20): 1.
10. The process for producing spermine according to claim 1, wherein the weight ratio of the second catalyst in S4 to 1,2,7,8,10,11,12,13-octahydropyrido [1,2-a ] [1,2,6,7] tetrazine is (0.05-1): 1.
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