CN114591258A - Preparation and purification method of cycleanine - Google Patents
Preparation and purification method of cycleanine Download PDFInfo
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- CN114591258A CN114591258A CN202210061796.6A CN202210061796A CN114591258A CN 114591258 A CN114591258 A CN 114591258A CN 202210061796 A CN202210061796 A CN 202210061796A CN 114591258 A CN114591258 A CN 114591258A
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- 238000000034 method Methods 0.000 title claims abstract description 41
- ANOXEUSGZWSCQL-LOYHVIPDSA-N Cycleanine Chemical compound C([C@H]1N(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3N(C)CCC=4C=C(OC)C(OC)=C(C3=4)O3)C=21)OC)OC)C1=CC=C3C=C1 ANOXEUSGZWSCQL-LOYHVIPDSA-N 0.000 title claims abstract description 20
- PEVPVMCJEMVCAS-UHFFFAOYSA-N Cycleanine Natural products COc1cc2CCN(C)C3Cc4ccc(Oc5cccc6CCN(C)C(Cc7ccc(Oc(c1OC)c23)cc7)c56)cc4 PEVPVMCJEMVCAS-UHFFFAOYSA-N 0.000 title claims abstract description 20
- ANOXEUSGZWSCQL-UHFFFAOYSA-N O-Methyl-isochondodendrin Natural products O1C(C2=3)=C(OC)C(OC)=CC=3CCN(C)C2CC(C=C2)=CC=C2OC(C=23)=C(OC)C(OC)=CC=2CCN(C)C3CC2=CC=C1C=C2 ANOXEUSGZWSCQL-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000000746 purification Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 46
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 28
- 238000001816 cooling Methods 0.000 claims abstract description 27
- 239000000047 product Substances 0.000 claims abstract description 26
- 239000001257 hydrogen Substances 0.000 claims abstract description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 24
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- 238000010438 heat treatment Methods 0.000 claims abstract description 21
- 239000007787 solid Substances 0.000 claims abstract description 17
- 238000003756 stirring Methods 0.000 claims abstract description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- 238000001914 filtration Methods 0.000 claims abstract description 12
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229940073608 benzyl chloride Drugs 0.000 claims abstract description 11
- 150000001925 cycloalkenes Chemical class 0.000 claims abstract description 11
- 239000008367 deionised water Substances 0.000 claims abstract description 10
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 10
- 238000000967 suction filtration Methods 0.000 claims abstract description 10
- 238000010992 reflux Methods 0.000 claims abstract description 9
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 7
- 239000000706 filtrate Substances 0.000 claims abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000001301 oxygen Substances 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 claims description 29
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 239000012267 brine Substances 0.000 claims description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 11
- 239000000463 material Substances 0.000 description 9
- 238000005984 hydrogenation reaction Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 239000012264 purified product Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 125000003944 tolyl group Chemical group 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 238000006264 debenzylation reaction Methods 0.000 description 2
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 2
- 229940015043 glyoxal Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms 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
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention relates to the field of organic synthesis, and discloses a preparation and purification method of cycleanine, which comprises the following steps: (1) sequentially adding benzyl chloride, tetrabenzyl cycloolefin and a catalyst into a reaction kettle, adding deionized water, and introducing nitrogen to remove oxygen; (2) introducing hydrogen into the reaction kettle, reacting at normal temperature until the hydrogen pressure is unchanged, and then increasing the temperature and the pressure to continue the reaction; (3) after the reaction is finished, filtering a reaction product under the protection of nitrogen, standing and layering the filtrate, and taking a water layer; (4) adding sodium hydroxide into the obtained water layer, heating, stirring, reacting, cooling to 4-6 ℃, and performing suction filtration to obtain wet solids; (5) adding toluene into the wet solid, and heating, refluxing and dehydrating; (6) and cooling and crystallizing the dehydrated product, filtering and drying to obtain the purified cycleanine. The method for preparing cycleanine by debenzylating tetrabenzyl cycloolefins serving as raw materials has the advantages of simple and convenient operation, mild conditions, short synthesis period, high product yield and purity, and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation and purification method of cycleanine.
Background
Cyclen (1,4,7, 10-tetraazacyclododecane, CAS number 294-90-6) is a polynitroazamacrocycloalkane, has strong coordination ability with various metal ions, can form various derivatives with side chain groups such as ester, amide, pyridine and the like, and can be used in different fields such as medicines, enzyme mimics, molecular recognition and the like.
The synthesis of cyclen is very difficult, and the synthesis methods of cyclen reported in the literature at present mainly include 6 methods: the Stetter method, the Richmann Atkins method, the Weisman-Reed method, the glyoxal condensation method, the diethyl oxalate condensation method and the acetal method. The Stetter method is only suitable for a small amount of preparation and is rarely used at present; the raw materials and reagents adopted by the Weisman-Reed method are expensive, and are not suitable for large-scale industrial production; the raw materials for synthesizing cycleanine by the glyoxal condensation method are cheap, the steps are few, the yield is high, but the reaction time is long, high-pressure hydrolysis is needed, and the method is not suitable for industrial production; the two-step yield of the diethyl oxalate condensation method is too low (39 percent and 56 percent), and the quality requirement of the cycleanine product cannot be met; the purification and preservation of raw materials by the acetal method are difficult, which is not beneficial to industrialization.
In view of the defects of the existing preparation method of cyclen, the development of a cyclen production and purification method which is simple and convenient to operate, mild in condition, short in synthesis period and suitable for industrial production has important significance.
Disclosure of Invention
In order to overcome the problems of the existing preparation method of cyclen, the invention provides a preparation and purification method of cyclen, which is used for preparing cyclen by debenzylating tetrabenzyl cycloolefines as raw materials, has the advantages of simple and convenient operation, mild conditions, short synthesis period, high product yield and purity, and is suitable for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation and purification method of cycleanine comprises the following steps:
(1) sequentially adding benzyl chloride, tetrabenzyl cycloolefine and a catalyst into a reaction kettle, adding deionized water, and introducing nitrogen to remove oxygen;
(2) introducing hydrogen into the reaction kettle, reacting at normal temperature until the hydrogen pressure is unchanged, and then increasing the temperature and the pressure to continue the reaction;
(3) after the reaction is finished, filtering a reaction product under the protection of nitrogen, standing and layering the filtrate, and taking a water layer;
(4) adding sodium hydroxide into the obtained water layer, heating, stirring, reacting, cooling to 4-6 ℃, and performing suction filtration to obtain wet solids;
(5) adding toluene into the wet solid, and heating, refluxing and dehydrating;
(6) and cooling and crystallizing the dehydrated product, filtering and drying to obtain the purified cycleanine.
The invention firstly uses tetrabenzyl cycloolefines as raw materials to perform debenzylation through the steps (1) and (2), and uses benzyl chloride to dechlorinate under the reaction condition and generate hydrogen chloride and amine in situ to react and form salt; the debenzylation can be carried out under the condition of no acid, thereby reducing the production cost and the damage to a reaction kettle. After the reaction is finished, filtering to remove the catalyst in the step (3), and then adding caustic soda flakes in the step (4) to convert the product from hydrochloride of amine into amine to obtain a crude product of cyclen; and (5) dehydrating and recrystallizing the product in the steps (5) and (6) to obtain the purified cyclen.
The method has the advantages of simple and convenient operation, mild conditions, short synthesis period, thorough reaction, highest product yield of 90 percent and purity of more than 99.5 percent, and is suitable for industrial production.
Preferably, the molar ratio of the benzyl chloride to the tetrabenzyl cycloolefin in the step (1) is 4-4.2: 1.
Preferably, the catalyst in the step (1) is a palladium-carbon catalyst, and the mass content of palladium in the palladium-carbon catalyst is 5-10%; the mass ratio of the catalyst to the tetrabenzyl cycloalkene is 0.05-0.1: 1.
Preferably, the mass of the deionized water added in the step (1) is 3.5-4 times of the theoretical mass of the cyclen. The generated hydrochloride is difficult to dissolve when the water is added too little; excessive water is added, the batch product quantity is small, and the later-stage product can be dissolved in water, so that the precipitation is not good and the yield is influenced.
Preferably, in the step (2), firstly, introducing hydrogen into the reaction kettle until the hydrogen pressure is 0.1-0.2 Mpa, reacting at normal temperature until the hydrogen pressure is unchanged, and removing 2-3 benzyl groups in the raw materials; and then heating to 65-75 ℃, increasing the pressure to 0.35-0.45 MPa, continuing the reaction, and removing the fourth benzyl.
Preferably, the mass of the sodium hydroxide added in the step (4) is 0.9-1.2 times of the theoretical mass of the cyclen. Sodium hydroxide is added excessively, and sodium hydroxide is brought out in the crystallization process of the product; and other impurities can not be dissolved in water and can enter the product to influence the purity of the product. The sodium hydroxide is added too little, so that the product cannot be fully separated out, and the product yield is influenced.
Preferably, in the step (4), the temperature is raised to 85-95 ℃, and the stirring reaction is carried out for 1-2 hours. The heating can promote the full reaction of the hydrochloride of the product and the sodium hydroxide, so that the product is completely dissociated.
Preferably, the mass of the toluene added in the step (5) is 2.8-3.5 times of the theoretical mass of the cyclen. Excessive solvent is added, the crystallization amount is small, and the product yield is low; if the solvent is added too little, the purity of the product is lowered.
Preferably, the reflux temperature in the step (5) is 90-110 ℃.
Preferably, in the cooling crystallization process in the step (6), the temperature is naturally cooled when the system temperature is more than or equal to 30 ℃, and is reduced to 0 ℃ by using brine when the system temperature is less than 30 ℃, and the temperature is kept for more than 8 hours.
Therefore, the invention has the following beneficial effects: the preparation method of cyclen by debenzylating tetrabenzyl cycloolefines as raw materials has the advantages of simple and convenient operation, mild condition, short synthesis period, high product yield and purity, and suitability for industrial production.
Detailed Description
The invention is further described with reference to specific embodiments.
The tetrabenzylcycloalkenes used in the present invention are synthesized based on the following route:
general example:
a preparation and purification method of cycleanine comprises the following steps:
(1) sequentially adding benzyl chloride, tetrabenzyl cycloolefine and a catalyst into a reaction kettle, adding deionized water, and introducing nitrogen to remove oxygen; wherein the molar ratio of benzyl chloride to tetrabenzyl cycloalkene is 4-4.2: 1, and the mass content of palladium in the palladium-carbon catalyst is 5-10%; the mass ratio of the palladium-carbon catalyst to the tetrabenzyl cycloolefin is 0.05-0.1: 1; the mass of the deionized water is 3.5-4 times of the theoretical mass of the cyclen;
(2) introducing hydrogen into the hydrogenation reaction kettle until the hydrogen pressure is 0.1-0.2 MPa; reacting at normal temperature until the hydrogen pressure is unchanged, then heating to 65-75 ℃, raising the pressure to 0.35-0.45 MPa, and continuing to react until the reaction is finished;
(3) cooling to below 60 ℃ after the reaction is finished, filtering a reaction product under the protection of nitrogen, standing and layering the filtrate, and taking a water layer;
(4) adding sodium hydroxide with the mass being 0.9-1.2 times of that of the theoretical cyclen into the obtained water layer, heating to 85-95 ℃, stirring for reaction for 1-2 hours, cooling to 4-6 ℃, and performing suction filtration to obtain wet solids;
(5) adding toluene with the mass 2.8-3.5 times of that of the theoretically obtained cyclen into the wet solid, and heating to 90-110 ℃ for reflux dehydration;
(6) and (3) cooling and crystallizing the dehydrated product, filtering and drying to obtain the purified cyclen, wherein in the cooling and crystallizing process, the temperature is naturally cooled when the system temperature is more than or equal to 30 ℃, and is reduced to 0 ℃ by using saline water when the system temperature is less than 30 ℃, and the temperature is kept for more than 8 hours.
Example 1:
a preparation and purification method of cycleanine comprises the following steps:
(1) sequentially adding 26.6g (0.21mol) of benzyl chloride, 26.65g (0.05mol) of tetrabenzyl cycloolefin and 2.67g of 10 wt% palladium-carbon catalyst into a hydrogenation reaction kettle, adding 30g of deionized water, and introducing nitrogen for 6 times;
(2) setting the reaction temperature at 25 ℃, introducing hydrogen into the hydrogenation reaction kettle until the hydrogen pressure is 0.2MPa, stirring, starting the reaction, and gradually reducing the reaction pressure; after the pressure is unchanged, heating to 67 ℃, increasing the reaction pressure first, then reducing, continuously introducing hydrogen, and keeping the reaction pressure at 0.4Mpa until the sampling detection reaction is finished;
(3) after the reaction is finished, cooling the materials to 60 ℃, filtering the reaction product under the protection of nitrogen, recovering the palladium-carbon catalyst, and standing and layering the filtrate, wherein the upper layer is a toluene layer, and the lower layer is a water layer;
(4) 10g of sodium hydroxide is added into the obtained water layer, and the material is white turbid; heating to 95 ℃, reacting until the materials are clear, continuously stirring for 1h, cooling to 5 ℃ for crystallization, and performing suction filtration to obtain wet solids;
(5) adding 26g of toluene into the wet solid, and heating to 100 ℃ for reflux dehydration;
(6) naturally cooling to 30 ℃, and stirring for 1 minute every 30 minutes; after the temperature is reduced to 30 ℃, a large amount of solid is separated out; and cooling the mixture to 0 ℃ by introducing cooling saline water, continuously stirring the mixture, keeping the temperature for 8 hours, and performing suction filtration and drying on the mixture to obtain 7.75g of a purified product.
Example 2:
a preparation and purification method of cycleanine comprises the following steps:
(1) sequentially adding 25.3g (0.2mol) of benzyl chloride, 26.65g (0.05mol) of tetrabenzyl cycloolefin and 2.67g of 10 wt% palladium-carbon catalyst into a hydrogenation reaction kettle, adding 34g of deionized water, and introducing nitrogen for replacement for 6 times;
(2) setting the reaction temperature at 25 ℃, introducing hydrogen into the hydrogenation reaction kettle until the hydrogen pressure is 0.2MPa, stirring, starting the reaction, and gradually reducing the reaction pressure; after the pressure is unchanged, heating to 67 ℃, increasing the reaction pressure first, then reducing, continuously introducing hydrogen, and keeping the reaction pressure at 0.4Mpa until the sampling detection reaction is finished;
(3) after the reaction is finished, cooling the materials to 60 ℃, filtering the reaction product under the protection of nitrogen, recovering the palladium-carbon catalyst, and standing and layering the filtrate, wherein the upper layer is a toluene layer, and the lower layer is a water layer;
(4) 10g of sodium hydroxide is added into the obtained water layer, and the material is white turbid; heating to 95 ℃, reacting until the materials are clear, continuously stirring for 1h, cooling to 5 ℃ for crystallization, and performing suction filtration to obtain wet solids;
(5) adding 24g of toluene into the wet solid, and heating to 90 ℃ for reflux dehydration;
(6) naturally cooling to 30 ℃, and stirring for 1 minute every 30 minutes; after the temperature is reduced to 30 ℃, a large amount of solid is separated out; and cooling the mixture to 0 ℃ by introducing cooling saline water, continuously stirring, keeping the temperature for 8 hours, and performing suction filtration and drying to obtain 7.50g of a purified product.
Example 3:
a preparation and purification method of cycleanine comprises the following steps:
(1) sequentially adding 26.6g (0.21mol) of benzyl chloride, 26.65g (0.05mol) of tetrabenzyl cycloolefin and 2.67g of 5 wt% palladium-carbon catalyst into a hydrogenation reaction kettle, adding 30g of deionized water, and introducing nitrogen for 6 times;
(2) setting the reaction temperature to be 20-25 ℃, introducing hydrogen into the hydrogenation reaction kettle until the hydrogen pressure is 0.2MPa, stirring, starting the reaction, and gradually reducing the reaction pressure; after the pressure is unchanged, heating to 75 ℃, increasing the reaction pressure first, then reducing, continuously introducing hydrogen, and keeping the reaction pressure at 0.4Mpa until the sampling detection reaction is finished;
(3) after the reaction is finished, cooling the materials to 60 ℃, filtering the reaction product under the protection of nitrogen, recovering the palladium-carbon catalyst, and standing and layering the filtrate, wherein the upper layer is a toluene layer, and the lower layer is a water layer;
(4) 8.6g of sodium hydroxide is added into the obtained water layer, and the material is white turbid; heating to 95 ℃, reacting until the materials are clear, continuously stirring for 1h, cooling to 5 ℃ for crystallization, and performing suction filtration to obtain wet solids;
(5) adding 26g of toluene into the wet solid, and heating to 110 ℃ for reflux dehydration;
(6) naturally cooling to 30 ℃, and stirring for 1 minute every 30 minutes; after the temperature is reduced to 30 ℃, a large amount of solid is separated out; and cooling the mixture to 0 ℃ by introducing cooling saline water, continuously stirring the mixture, keeping the temperature for 8 hours, and performing suction filtration and drying on the mixture to obtain 7.20g of a purified product.
The yield and purity of the product obtained in the above example were calculated and measured, and the results are shown in table 1.
Table 1: and testing the product yield and purity.
| Example 1 | Example 2 | Example 3 | |
| Yield (%) | 90 | 87 | 83.5 |
| Purity (%) | 99.69 | 99.77 | 99.92 |
The results show that the method is simple and convenient to operate, mild in condition, short in synthesis period and suitable for industrial production; and the prepared product has high yield and purity, and meets the product quality requirement.
Claims (10)
1. A preparation and purification method of cycleanine is characterized by comprising the following steps:
(1) sequentially adding benzyl chloride, tetrabenzyl cycloolefine and a catalyst into a reaction kettle, adding deionized water, and introducing nitrogen to remove oxygen;
(2) introducing hydrogen into the reaction kettle, reacting at normal temperature until the hydrogen pressure is unchanged, and then increasing the temperature and the pressure to continue the reaction;
(3) after the reaction is finished, filtering a reaction product under the protection of nitrogen, standing and layering the filtrate, and taking a water layer;
(4) adding sodium hydroxide into the obtained water layer, heating, stirring, reacting, cooling to 4-6 ℃, and performing suction filtration to obtain wet solids;
(5) adding toluene into the wet solid, and heating, refluxing and dehydrating;
(6) and cooling and crystallizing the dehydrated product, filtering and drying to obtain the purified cycleanine.
2. The method for preparing and purifying cyclen according to claim 1, wherein the molar ratio of benzyl chloride to tetrabenzyl cyclo olefin in step (1) is 4-4.2: 1.
3. The method for preparing and purifying cycleanine according to claim 1 or 2, wherein the catalyst in the step (1) is a palladium-carbon catalyst, and the mass content of palladium in the palladium-carbon catalyst is 5-10%; the mass ratio of the catalyst to the tetrabenzyl cycloalkene is 0.05-0.1: 1.
4. The method for preparing and purifying cyclen according to claim 1, wherein the mass of deionized water added in step (1) is 3.5-4 times of the theoretical cyclen mass.
5. The method for preparing and purifying cyclen according to claim 1, wherein hydrogen is introduced into the reaction kettle in the step (2) until the hydrogen pressure is 0.1-0.2 MPa; and (3) reacting at normal temperature until the hydrogen pressure is unchanged, heating to 65-75 ℃, increasing the pressure to 0.35-0.45 MPa, and continuing to react.
6. The method for preparing and purifying cyclen according to claim 1, wherein the mass of sodium hydroxide added in step (4) is 0.9-1.2 times of the theoretical mass of cyclen.
7. The method for preparing and purifying cycleanine according to claim 1 or 6, wherein the temperature in step (4) is increased to 85-95 ℃, and the cycleanine is stirred and reacted for 1-2 hours.
8. The method for preparing and purifying cyclen according to claim 1, wherein the mass of toluene added in step (5) is 2.8-3.5 times of the theoretical mass of cyclen.
9. The method for preparing and purifying cycleanine according to claim 1 or 8, wherein the reflux temperature in step (5) is 90-110 ℃.
10. The method for preparing and purifying cyclen according to claim 1, wherein in the cooling crystallization process in step (6), the temperature is naturally cooled when the system temperature is higher than or equal to 30 ℃, and is reduced to 0 ℃ by using brine when the system temperature is lower than 30 ℃, and the temperature is kept for more than 8 hours.
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| CN202210061796.6A CN114591258B (en) | 2022-01-19 | 2022-01-19 | Preparation and purification method of Xuancyclic vine |
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| CN202210061796.6A CN114591258B (en) | 2022-01-19 | 2022-01-19 | Preparation and purification method of Xuancyclic vine |
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| CN114591258A true CN114591258A (en) | 2022-06-07 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1181751A (en) * | 1995-03-10 | 1998-05-13 | 耐克麦德瑟鲁塔公司 | Prepn. of N-arylmethyl axiridine derivatives, 1, 4, 7, 10 -Tetraazacyclododecane derivatives obtained therefrom and N -arylmethyl -ethanol -amine sulphonate esters as intermediates |
| FR2810035A1 (en) * | 2000-06-13 | 2001-12-14 | Air Liquide | Synthesis of macrocyclic polyamine compounds, useful as agents for purification of liquids, as catalysts and in medicinal applications |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1181751A (en) * | 1995-03-10 | 1998-05-13 | 耐克麦德瑟鲁塔公司 | Prepn. of N-arylmethyl axiridine derivatives, 1, 4, 7, 10 -Tetraazacyclododecane derivatives obtained therefrom and N -arylmethyl -ethanol -amine sulphonate esters as intermediates |
| FR2810035A1 (en) * | 2000-06-13 | 2001-12-14 | Air Liquide | Synthesis of macrocyclic polyamine compounds, useful as agents for purification of liquids, as catalysts and in medicinal applications |
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