CN113072514B - Preparation method of Xuanjinning and intermediate thereof - Google Patents
Preparation method of Xuanjinning and intermediate thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 94
- 238000000034 method Methods 0.000 claims abstract description 54
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical group OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000006722 reduction reaction Methods 0.000 claims abstract description 23
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 22
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 63
- 239000002904 solvent Substances 0.000 claims description 62
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 46
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 44
- 239000003960 organic solvent Substances 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 229940015043 glyoxal Drugs 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 19
- 239000007864 aqueous solution Substances 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 10
- 239000012964 benzotriazole Substances 0.000 claims description 10
- 239000003638 chemical reducing agent Substances 0.000 claims description 10
- 238000007259 addition reaction Methods 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 150000008282 halocarbons Chemical class 0.000 claims description 8
- 150000002825 nitriles Chemical class 0.000 claims description 8
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 7
- 150000002576 ketones Chemical class 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims 2
- 239000005456 alcohol based solvent Substances 0.000 claims 1
- 239000003759 ester based solvent Substances 0.000 claims 1
- 239000005453 ketone based solvent Substances 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 abstract description 24
- 229910000147 aluminium phosphate Inorganic materials 0.000 abstract description 12
- 239000000543 intermediate Substances 0.000 abstract description 11
- 238000000746 purification Methods 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 6
- 238000001914 filtration Methods 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000012065 filter cake Substances 0.000 description 14
- 238000005406 washing Methods 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 10
- 238000011085 pressure filtration Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000001308 synthesis method Methods 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000012452 mother liquor Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 230000007547 defect Effects 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 229940080817 rotenone Drugs 0.000 description 3
- JUVIOZPCNVVQFO-UHFFFAOYSA-N rotenone Natural products O1C2=C3CC(C(C)=C)OC3=CC=C2C(=O)C2C1COC1=C2C=C(OC)C(OC)=C1 JUVIOZPCNVVQFO-UHFFFAOYSA-N 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241000700141 Rotifera Species 0.000 description 2
- 238000007296 Stetter synthesis reaction Methods 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 239000003849 aromatic solvent Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- OAEGRYMCJYIXQT-UHFFFAOYSA-N dithiooxamide Chemical compound NC(=S)C(N)=S OAEGRYMCJYIXQT-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 description 1
- LHWZLUXODWUHLZ-UHFFFAOYSA-N 4-methyl-n-(4-methylphenyl)sulfonylbenzenesulfonamide Chemical class C1=CC(C)=CC=C1S(=O)(=O)NS(=O)(=O)C1=CC=C(C)C=C1 LHWZLUXODWUHLZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000009007 Diagnostic Kit Methods 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000002059 diagnostic imaging Methods 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- TWOKQHDORBJKRS-UHFFFAOYSA-N n'-[2-[2-(ethylamino)ethylamino]ethyl]ethane-1,2-diamine Chemical compound CCNCCNCCNCCN TWOKQHDORBJKRS-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000005298 paramagnetic effect Effects 0.000 description 1
- YBVNFKZSMZGRAD-UHFFFAOYSA-N pentamidine isethionate Chemical compound OCCS(O)(=O)=O.OCCS(O)(=O)=O.C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 YBVNFKZSMZGRAD-UHFFFAOYSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000006049 ring expansion reaction Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229940126585 therapeutic drug Drugs 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
-
- 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
- C07D487/22—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 four or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing a Xuancyclic vine extract and an intermediate thereof. The invention specifically discloses a preparation method of a compound shown as a formula 4, which comprises the following steps: in water, carrying out the reduction reaction of the compound shown in the formula 3 and hydrazine hydrate as follows; wherein X is phosphoric acid or sulfuric acid; when X is phosphoric acid, n is 4/3; when X is sulfuric acid, n is 2. The preparation method of the invention has low cost, simple and convenient operation, easy purification of intermediates and products, high yield and purity, and suitability for industrial production.
Description
Technical Field
The invention relates to the field of chemical synthesis, in particular to a preparation method of a Xuancyclic vine extract and an intermediate thereof.
Background
Cyclovine (1, 4,7, 10-tetraazadodecane, cyclen) is a white or nearly white crystalline powder chemical. Molecular formula C 8 H 20 N 4 The molecular weight is 172.28. Is an important intermediate for synthesizing therapeutic drugs of diagnostic kits. It is used for removing calculus in human body, especially for preparing contrast agent for medical imaging technology such as Magnetic Resonance Imaging (MRI), X-ray CT, ultrasonic imaging, etc., and radiopharmaceutical for treating malignant tumor, and its derivatives are all shown to be extremely highThe important application value is provided. The complex can be used as a precursor of a macrocyclic chelating agent for synthesizing metal ions, can form a very stable complex with ions, particularly paramagnetic metal ions, can be used in the field of medical diagnosis, does not generate high toxicity caused by free ions, and has the safety characteristic. The ageing in the world is more and more serious, the demand of the Xuanjinning is also more and more great, and the compound has wide market prospect, but only a few factories produce the compound in the world at present, and the purity of the product is not high.
Currently, the chemical synthesis methods of the rotenone are mainly a Stetter synthesis method, a Richman-Atkins synthesis method, a Weisman synthesis method, a glyoxal condensation method and a diethyl oxalate synthesis method.
Stetter synthesis method
The first general method for synthesizing macrocyclic polyamines was proposed by Stetter and Max in 1957 (Stetter, h.; marx, j. Chem. Brit.1957,607, 59), the Stetter method uses the condensation of the di-p-toluenesulfonamide derivative of ethylenediamine diacetic chloride with ethylenediamine in highly diluted conditions (about 0.001 mol/L) to close the ring, followed by reduction and deprotection to give the target product. The method has the advantages that the raw materials required by the method are not easy to obtain, and the method is rarely adopted at present because the ring closure is carried out under the condition of high dilution, the reaction yield is not high, the productivity is limited, and the method is not suitable for industrial mass preparation.
Richman-Atkins synthesis method
For many years, the synthesis of Xuan vine by the Richman-Atkins method (Richman, J.E.; atkins, T.J.J.am.chem.Soc.1974,96,2268) has been the classical method for preparing Xuan vine. The method uses diethyl triamine and diethanolamine to prepare the rotifer by 5 steps of p-toluenesulfonylation, salification, ring closure, deprotection, alkalization extraction and the like. The method has high yield and large synthesis amount, and is one of the main ways of preparing the rotifer at present in a laboratory. However, the method has the advantages of more experimental steps, large consumption of reagents for protection and deprotection, low atom utilization rate and inconvenient operation, and is not an ideal industrialized synthetic route.
Weisman synthesis method
The Richman-Atkins synthesis described above requires removal of four p-toluenesulfonyl groups during the synthesis, which is not in line with the principles of atom economy. After this disadvantage is noted, weisman et al propose a novel method for synthesizing Xuan Ganning (Weisman, G.R.Org.chem.1997,62,4548). Directly reacting dithiooxamide with triethylenetetramine to obtain tricyclic diamidine, then performing double reduction by diisobutylaluminum hydride (DIBALH), and obtaining the Xuan vine ning after ring expansion, wherein the total yield is 67%.
The route does not need a protecting group, is completed in two steps, has high product yield and purity, and is particularly easy to realize in a laboratory. Compared with the Richman-Atkins method, the method has the defects that the dithiooxamide as the initial raw material is quite expensive, hydrogen sulfide is generated in the reaction, DIBALH used in the reduction step is relatively expensive, the method is sensitive to moisture, special care is needed in operation, and the method is limited by the factors and is only suitable for small-scale synthesis.
Glyoxal condensation method
Glyoxal condensation is a new method developed in recent years. The method comprises the steps of preparing the rotenone by condensing glyoxal aqueous solution with triethylenetetramine (Herv, G. Tetrahedron Lett.1999,40,2517), wherein the common point is that one or more rigid intermediates which are isomers are obtained firstly, and then cyclizing and deprotection steps are carried out to obtain the rotenone. The method has the advantages of easily available raw materials, low cost, mild reaction conditions and simpler product purification.
The biggest problem with this route is that during the further cyclization of the rigid intermediate and dibromoethane, the cyclization reaction is competitive with the reaction of dibromoethane with tertiary amines to form quaternary ammonium salts, resulting in low yields. The amplification effect in the industrial production process is more difficult to control for the side reaction, so that the strategy of forming a rigid intermediate by taking triethylenetetramine as a starting material is not suitable for the scale-up production.
Diethyl oxalate synthesis method
The method has little research, and the triethylenetetramine and diethyl oxalate are adopted for condensation ring closure (Wei, J. -F.chem.J.Chin.Univ.1997,18,658) and diborane is used for reduction to obtain the product. The condensation cyclization reaction of triethylenetetramine and diethyl oxalate also has the defects that the reaction needs to be carried out at a thinner concentration and is not suitable for industrial production.
The above routes have great defects in the aspects of raw materials or processes, and bring certain difficulties to the industrial production of the Xuan vine.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defect of single variety of the existing synthetic route of the Xuan vine, and provide a preparation method of the Xuan vine and the intermediate thereof. The preparation method of the invention has low cost, simple and convenient operation, easy purification of intermediates and products, high yield and purity, and suitability for industrial production.
The invention solves the technical problems through the following technical proposal.
The invention provides a preparation method of a compound shown as a formula 4, which comprises the following steps: in water, carrying out the reduction reaction of the compound shown in the formula 3 and hydrazine hydrate as follows;
wherein X is phosphoric acid or sulfuric acid;
when X is phosphoric acid, n is 4/3;
when X is sulfuric acid, n is 2.
In the preparation method of the compound shown in the formula 4, X is preferably sulfuric acid.
In the preparation method of the compound shown in the formula 4, the water and the hydrazine hydrate can be added in the form of a hydrazine hydrate aqueous solution. The aqueous hydrazine hydrate solution may be a conventional mass fraction aqueous hydrazine hydrate solution in the art, preferably a 50% -80% mass fraction aqueous hydrazine hydrate solution, for example a 50% or 80% mass fraction aqueous hydrazine hydrate solution.
In the preparation method of the compound shown in the formula 4, the molar ratio of the hydrazine hydrate to the compound shown in the formula 3 can be a conventional molar ratio in the field, preferably 3:1-5:1, for example 3:1 or 5:1.
In the preparation method of the compound shown in formula 4, the temperature of the reduction reaction may be a temperature conventional in the art, preferably 60 to 100 ℃, more preferably 80 to 90 ℃, for example 90 ℃.
In the preparation of the compound of formula 4, the progress of the reduction reaction may be monitored by means conventional in the art (e.g. TLC, HPLC, GC or NMR, preferably GC), and the duration of the reduction reaction is preferably from 12 to 96 hours, more preferably from 12 to 30 hours, for example 12 hours.
The preparation method of the compound shown in the formula 4 can further comprise the following steps: in an organic solvent, carrying out salt forming reaction on a compound shown in a formula 2 and X as follows;
wherein n and X are as defined above.
In the salt-forming reaction, the organic solvent may be one or more of a conventional organic solvent in the art, preferably a halogenated hydrocarbon solvent, a nitrile solvent, a ketone solvent, an ester solvent and an alcohol solvent, more preferably an alcohol solvent. The halogenated hydrocarbon solvent is preferably methylene dichloride. The nitrile solvent is preferably acetonitrile. The ketone solvent is preferably acetone. The ester solvent is preferably ethyl acetate. The alcohol solvent is preferably one or more of methanol, ethanol, propanol and butanol, more preferably ethanol.
In the salt forming reaction, when X is phosphoric acid, the phosphoric acid can be added in the form of an aqueous phosphoric acid solution. The phosphoric acid aqueous solution may be a phosphoric acid aqueous solution of a mass fraction conventional in the art, preferably a phosphoric acid aqueous solution of 65 to 85% by mass, more preferably a phosphoric acid aqueous solution of 85% by mass.
In the salt forming reaction, X is preferably sulfuric acid. The sulfuric acid may be added in the form of an aqueous sulfuric acid solution. The aqueous sulfuric acid solution may be an aqueous sulfuric acid solution of a mass fraction conventional in the art, preferably an aqueous sulfuric acid solution of 80 to 98% by mass, more preferably an aqueous sulfuric acid solution of 98% by mass.
In the salt-forming reaction, the molar ratio of X to the compound of formula 2 may be in a molar ratio conventional in the art, preferably 1:1 to 6:1, for example 2.15:1, 2.37:1 or 6:1.
In the salification reaction, the ratio of the organic solvent to the compound represented by formula 2 may be a ratio of volume to mass as is conventional in the art, preferably 1 to 50mL/g, more preferably 1 to 20mL/g, still more preferably 5 to 20mL/g, still more preferably 15 to 20mL/g, for example 17.86mL/g.
In the salt formation reaction, the salt formation reaction temperature can be the field conventional temperature, preferably-20-20 ℃, more preferably-10-10 ℃, even more preferably 0-10 ℃, such as 0 ℃.
In the salt formation reaction, the progress of the salt formation reaction can be monitored by means conventional in the art (e.g. TLC, HPLC, GC or NMR, preferably GC), and the salt formation reaction is preferably carried out for a period of time of from 5 to 40 hours, more preferably from 5 to 10 hours, for example 5 hours.
The post-treatment of the salt formation reaction may be conventional in the art, comprising the steps of: filtering the reaction solution, washing the filter cake, and drying. The washing solvent is preferably an alcoholic solvent such as ethanol.
The preparation method of the compound shown in the formula 4 can further comprise the following steps:
(1) In an organic solvent and water, in the presence of benzotriazole, carrying out an addition reaction on a compound shown as a formula 1 and glyoxal to obtain a reaction liquid 1;
(2) Carrying out reduction reaction on the reaction liquid 1 in the step (1) in the presence of a reducing agent;
in the step (1), the organic solvent may be one or more of organic solvents conventional in the art, preferably an alcohol solvent, an ether solvent, an ester solvent, a nitrile solvent, a halogenated hydrocarbon solvent, a ketone solvent and an aromatic hydrocarbon solvent, more preferably an alcohol solvent. The alcohol solvent is preferably one or more of ethanol, methanol and isopropanol, and more preferably ethanol. The ether solvent is preferably methyl tertiary butyl ether. The ester solvent is preferably ethyl acetate and/or isopropyl acetate. The nitrile solvent is preferably acetonitrile. The halogenated hydrocarbon solvent is preferably methylene dichloride. The ketone solvent is preferably acetone. The aromatic hydrocarbon solvent is preferably toluene and/or xylene.
In step (1), the water and the glyoxal may be added in the form of an aqueous glyoxal solution, which may be an aqueous glyoxal solution of a mass fraction conventional in the art, preferably an aqueous glyoxal solution of 10% to 40% by mass, for example an aqueous glyoxal solution of 40% by mass.
In step (1), the molar ratio of glyoxal to the compound of formula 1 may be a molar ratio conventional in the art, preferably from 2:1 to 8:1, more preferably from 2:1 to 3:1, for example 2:1.
In step (1), the molar ratio of the benzotriazole to the compound of formula 1 may be a molar ratio conventional in the art, preferably 2:1 to 8:1, more preferably 2:1 to 3:1, for example 2:1.
In step (1), the ratio of the organic solvent to the compound represented by formula 1 may be a ratio of volume to mass as is conventional in the art, preferably 3 to 30mL/g, more preferably 3 to 9mL/g, still more preferably 3 to 6mL/g, for example 4mL/g.
In step (1), the temperature of the addition reaction may be a temperature conventional in the art, preferably-20℃to the reflux temperature of the organic solvent at normal pressure, more preferably 0-20℃such as 0 ℃.
In step (1), the addition reaction may be monitored by means conventional in the art (e.g. TLC, HPLC, GC or NMR, preferably GC) and the time of the addition reaction is preferably 3 to 72 hours, more preferably 3 to 12 hours, for example 3 hours.
In step (2), the reducing agent may be a reducing agent conventional in the art, preferably one or more of sodium borohydride, lithium aluminum hydride, hydrogen, hydrazine hydrate, ammonium formate, formic acid and triethylamine formic acid azeotrope, more preferably sodium borohydride.
In step (2), the molar ratio of the reducing agent to the compound of formula 1 in step (1) may be a molar ratio conventional in the art, preferably 2:1 to 20:1, more preferably 2:1 to 4:1, for example 2:1.
In step (2), the temperature of the reduction reaction may be a reaction temperature conventional in the art, preferably a reflux temperature of the organic solvent at 0℃to normal pressure, more preferably 0 to 20℃such as 0 ℃.
In step (2), the reduction reaction may be monitored by means conventional in the art (e.g. TLC, HPLC, GC or NMR, preferably GC) and the reduction reaction is preferably carried out for a period of 3 to 72 hours, more preferably 3 to 12 hours, for example 3 hours.
The work-up procedure for the reduction reaction may be a work-up conventional in the art comprising the steps of: removing organic solvent, removing water, filtering, and concentrating the filtrate. The method for removing the organic solvent is preferably concentration, more preferably reduced pressure/normal pressure concentration. The filtration operation may preferably be further included before the removal of the organic solvent. The water removal is preferably carried out by adding an organic solvent. The water diversion operation may be conventional in the art, preferably atmospheric reflux water diversion. The organic solvent added in the water separation operation is preferably an aromatic hydrocarbon solvent such as toluene. After the water removal is finished, the method can further comprise a cooling step, wherein the cooling is preferably carried out to 20-30 ℃, for example, 20 ℃. Preferably, the filter cake is further washed before concentrating the filtrate. The solvent for washing is preferably an aromatic hydrocarbon solvent such as toluene. The number of times of washing is preferably 1 to 2.
The invention provides a preparation method of a compound shown as a formula 5, which comprises the following steps:
(1) A compound represented by formula 4 according to any one of the above methods;
(2) The compound shown in the formula 4 obtained in the step (1) and alkali are subjected to neutralization reaction shown below;
wherein n and X are as defined above;
in the method for producing a compound represented by formula 5, in the step (1), the conditions and operations of the reduction reaction are the same as those of the aforementioned reaction.
In the method for preparing the compound represented by formula 5, in the step (2), the base may be a base conventional in the art, preferably an alkali metal hydroxide, more preferably sodium hydroxide.
In the preparation method of the compound shown in the formula 5, in the step (2), other conditions and parameters of the neutralization reaction are the same as those of the reaction in the field.
In the preparation method of the compound shown in the formula 5, in the step (2), the post-treatment of the neutralization reaction can be a conventional post-treatment in the field, which comprises the following steps: concentrating the reaction solution, adding solvent to extract concentrate, filtering the organic phase, concentrating, and recrystallizing. The concentration is preferably reduced pressure concentration. The solvent is preferably an aromatic hydrocarbon solvent such as toluene. The solvent for recrystallization is preferably an aromatic hydrocarbon solvent and/or an alkane solvent, the aromatic hydrocarbon solvent is preferably toluene, and the alkane solvent is preferably n-heptane.
The invention also provides a preparation method of the compound shown in the formula 2, which comprises the following steps:
(1) In an organic solvent and water, in the presence of benzotriazole, carrying out an addition reaction on a compound shown as a formula 1 and glyoxal to obtain a reaction liquid 1;
(2) Subjecting the reaction solution 1 obtained in step (1) to a reduction reaction in the presence of a reducing agent, and the post-treatment comprising the steps of: removing organic solvent, removing water, filtering, and concentrating; the water removal is water diversion water removal;
in the preparation method of the compound shown in the formula 2, in the step (1), the conditions and the operation of the addition reaction are the same as those of the reaction.
In the preparation method of the compound shown in the formula 2, in the step (2), the conditions and the operation of the reduction reaction are the same as those of the reaction.
In the preparation method of the compound shown in the formula 2, in the step (2), the method for removing the organic solvent may be a conventional method in the art, and preferably concentration under reduced pressure or concentration under normal pressure is preferred.
In the method for preparing the compound represented by formula 2, the step (2) of removing the organic solvent may preferably further comprise a filtration operation, and the filtration conditions and methods may be conventional in the art, such as reduced pressure filtration or normal pressure filtration.
In the preparation method of the compound shown in the formula 2, in the step (2), the water diversion operation can be a conventional operation in the field, and the water diversion is preferably reduced pressure reflux water diversion or normal pressure reflux water diversion, and more preferably normal pressure reflux water diversion. The organic solvent used in the water separation is preferably an aromatic solvent, and more preferably toluene.
In the preparation method of the compound shown in the formula 2, in the step (2), after the water removal is finished, a cooling step can be further included, and the cooling is preferably cooled to 20-30 ℃, for example, 20 ℃.
In the method for preparing the compound represented by formula 2, in the step (2), the filtration may be performed by a conventional process in the art, such as reduced pressure filtration or normal pressure filtration.
In the preparation method of the compound shown in the formula 2, in the step (2), after the filtration is finished, washing operation can be further included. The washing solvent is preferably an aromatic hydrocarbon solvent such as toluene. The number of times of washing is preferably 1 to 2.
In the preparation method of the compound shown in the formula 2, in the step (2), the concentration operation can be a conventional operation in the art, such as reduced pressure concentration or normal pressure concentration.
The invention also provides a method for purifying the compound shown in the formula 2, which comprises the following steps: the mixture comprising the compound represented by formula 2, an organic solvent and water is treated as follows: removing organic solvent, removing water, filtering, and concentrating; the water removal is water diversion water removal;
in the purification method of the compound represented by formula 2, the method of removing the organic solvent may be a method conventional in the art, preferably vacuum concentration or normal pressure concentration.
In the purification method of the compound represented by formula 2, the organic solvent may be removed preferably further comprising a filtration operation, and the filtration conditions and methods may be conventional in the art, such as reduced pressure filtration or normal pressure filtration.
In the purification method of the compound represented by formula 2, the operation of water diversion may be a conventional operation in the art, and the water diversion is preferably reduced pressure reflux water diversion or normal pressure reflux water diversion, more preferably normal pressure reflux water diversion. The organic solvent used in the water separation is preferably an aromatic solvent, and more preferably toluene.
In the method for purifying the compound shown in the formula 2, after the water removal is finished, a cooling step can be further included, and the cooling is preferably cooled to 20-30 ℃, for example, 20 ℃.
In the purification method of the compound represented by formula 2, the filtration may be performed by a conventional method in the art, such as reduced pressure filtration or normal pressure filtration.
In the method for purifying the compound of formula 2, the filtration is completed, and preferably, the method further comprises washing. The washing solvent is preferably an aromatic hydrocarbon solvent such as toluene. The number of times of washing is preferably 1 to 2.
In the purification method of the compound represented by formula 2, the concentration may be performed by a conventional method in the art, such as vacuum concentration or normal pressure concentration.
The invention also provides a compound shown as a formula 4-1 or a formula 4-2,
the above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
In the invention, "°c" refers to "degrees celsius", unless otherwise specified; "h" means "hour".
In the present invention, room temperature means 10 to 40℃unless otherwise specified.
The reagents and starting materials used in the present invention are commercially available unless otherwise specified.
The invention has the positive progress effects that: the preparation method of the invention has low cost, simple and convenient operation, easy purification of intermediates and products, high yield and purity, and suitability for industrial production.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1
100 g of triethylenetetramine and 163 g of benzotriazole are dissolved in 400mL of ethanol, 200 g of 40% glyoxal aqueous solution is added dropwise at 0 ℃, and the mixture is stirred for 3 hours at 0 ℃ to control the reaction to be qualified. 52 g of sodium borohydride are added at 0℃and stirred for 3 hours. After the reaction is controlled to be qualified, filtering to remove insoluble salt, concentrating the filtrate to remove ethanol, adding 600mL of toluene, heating to raise the temperature to perform normal pressure reflux water diversion, cooling to 20 ℃ after the water is completely removed, filtering to remove insoluble solid benzotriazole (for recovery, the recovery rate is 92%), washing a filter cake once by 100mL of toluene, combining the filtrates, concentrating the filtrate under reduced pressure until no obvious fraction is distilled off, thus obtaining 100 g of pale yellow oily compound of the formula 2, wherein the yield is 75%, and the content is about 70%. 1 H NMR(CDCl 3 ,400MHz):3.087(s,2H),2.959-2.875(m,8H),2.635-2.487(m,8H). 13 C NMR(CDCl 3 ,125.8MHz):77.43,51.04,50.26.GC-MS:194.
Example 2
56 g of the compound of formula 2 (100% pure) are dissolved in 1000mL of ethanol, cooled to 0℃and 68.6 g of 98% sulfuric acid are added dropwise, and stirred at 0℃for 5 hours. Filtering, washing the filter cake with ethanol, and drying the filter cake to obtain 107 g of the compound of the formula 3-1 with the yield of 95%. The purity of the compound 3-1 is not less than 96%, total nitrogen: 14.45%.
Example 3
56 g of the compound of formula 2 (100% pure) are dissolved in 1000mL of ethanol, cooled to 0℃and 173 g of 98% sulfuric acid are added dropwise, and stirred at 0℃for 5 hours. Filtering, washing a filter cake with ethanol, and drying the filter cake to obtain 108 g of the compound of the formula 3-1, wherein the yield is 95%.
Example 4
56 g of the compound of formula 2 (100% pure) are dissolved in 1000mL of ethanol, cooled to 0℃and 72 g of 85% phosphoric acid are added dropwise, and stirred at 0℃for 5 hours. Filtering, washing a filter cake with ethanol, and drying the filter cake to obtain 89 g of a compound of formula 3-2, wherein the yield is 95%, the purity of the compound 3-2 is not less than 96%, and the total nitrogen is as follows: 17.50%.
Example 5
100 g of the compound of formula 3-1 (100% pure) are dissolved in 80 g of 80% hydrazine hydrate, heated to 90℃and incubated for 12 hours. After completion of the medium control reaction, 31 g of sodium hydroxide was added, followed by concentrating under reduced pressure to remove the aqueous phase, and 200mL of toluene was added to extract the concentrated residue. Insoluble matters are removed by filtration, 200mL of toluene is added for recrystallization after the filtrate is concentrated, mother liquor is removed by filtration, and Ning Chanwu g of white cyclean is obtained after the filter cake is dried, the yield is 75%, and the purity is more than 99.5%. 1 H NMR(CDCl 3 ,400MHz):2.485-2.435(d,16H),1.832(s,4H). 13 C NMR(CDCl 3 ,125.8MHz):45.9.GC-MS:172.
Example 6
100 g of the compound of formula 3-1 (100% pure) are dissolved in 128 g of 50% hydrazine hydrate, heated to 90℃and incubated for 12 hours. After completion of the medium control reaction, 31 g of sodium hydroxide was added, followed by concentrating under reduced pressure to remove the aqueous phase, and 200mL of toluene was added to extract the concentrated residue. Insoluble matters are removed by filtration, 200mL of toluene is added for recrystallization after the filtrate is concentrated, mother liquor is removed by filtration, ning Chanwu g of white cyclean is obtained after the filter cake is dried, and the yield is 79 percent and the purity is more than 99.5 percent.
Example 7
100 g of the compound of formula 3-1 (100% pure) are dissolved in 48 g of 80% hydrazine hydrate, heated to 90℃and incubated for 12 hours. After completion of the medium control reaction, 31 g of sodium hydroxide was added, followed by concentrating under reduced pressure to remove the aqueous phase, and 200mL of toluene was added to extract the concentrated residue. Insoluble matters are removed by filtration, 200mL of toluene is added for recrystallization after the filtrate is concentrated, mother liquor is removed by filtration, ning Chanwu g of white cyclean is obtained after the filter cake is dried, and the yield is 73 percent and the purity is more than 99.5 percent.
Example 8
100 g of the compound of formula 3-2 (100% pure) are dissolved in 80 g of 80% hydrazine hydrate, heated to 90℃and incubated for 12 hours. After the completion of the medium-control reaction, 40 g of sodium hydroxide was added, followed by concentrating under reduced pressure to remove the aqueous phase, and 200mL of toluene was added to extract the residue. Insoluble substances are removed by filtration, 200mL of toluene is added for recrystallization after the filtrate is concentrated, mother liquor is removed by filtration, and Ning Chanwu g of white cycleana is obtained after the filter cake is dried, the yield is 55%, and the purity is more than 99.5%.
Comparative example 1
87 g of the starting compound (calculated as 100% purity) are dissolved in 80 g of 80% hydrazine hydrate, heated to 90℃and incubated for 12 hours. After completion of the medium control reaction, 31 g of sodium hydroxide was added, followed by concentrating under reduced pressure to remove the aqueous phase, and 200mL of toluene was added to extract the concentrated residue. Insoluble matters are removed by filtration, 200mL of toluene is added for recrystallization after the filtrate is concentrated, mother liquor is removed by filtration, and Ning Chanwu g of white cyclean is obtained after the filter cake is dried, and the yield is 43%.
Comparative example 2
The following compound 2 was synthesized by the method described in patent US 7659393B.
10g (68.4 mmol) triethylenetetramine and 16.3g (136.7 mmol) benzotriazole were dissolved in 200mL of water, cooled to 2℃and 80mL of glyoxal methanol solution (19.86 g (136.7 mmol) of glyoxal aqueous solution was added to 80mL of methanol) was slowly added dropwise thereto. After the completion of the dropwise addition, the temperature was raised to room temperature and stirred for 4 hours. Thereafter, 5.18g (136.7 mmol) of sodium borohydride was added in portions and stirred at room temperature for 2 hours. After the completion of the reaction, methanol was distilled off, and 13g of potassium hydroxide was added to the reaction system. The mixture was extracted with chloroform 400 mL. Times.3, and the organic phase was dried over anhydrous magnesium sulfate. The solvent was removed to give compound 2 (9 g, yield 68%, content about 70%) as a yellow oil.
In the actual operation process, the extraction process is extremely easy to generate emulsification phenomenon, is difficult to delaminate, has large loss of products, is complex to operate, consumes long time, and is difficult to recycle and reuse the benzotriazole.
Claims (12)
1. A method for preparing a compound represented by formula 5, comprising the steps of:
(3) In water, carrying out reduction reaction on the compound shown in the formula 3 and hydrazine hydrate as follows;
；
(4) The compound shown in the formula 4 obtained in the step (3) and alkali are subjected to neutralization reaction shown below;
wherein X is sulfuric acid;
n is 2;
the water and the hydrazine hydrate are added in the form of a hydrazine hydrate aqueous solution;
the hydrazine hydrate aqueous solution is 50-80% of hydrazine hydrate aqueous solution by mass fraction;
the molar ratio of the hydrazine hydrate to the compound shown in the formula 3 is 3:1-5:1;
the temperature of the reduction reaction is 60-100 ℃.
2. The method for preparing a compound represented by formula 5 according to claim 1, wherein the temperature of the reduction reaction is 80 to 90 ℃.
3. The method for preparing a compound represented by formula 5 according to claim 1 or 2, further comprising the steps of: in an organic solvent, carrying out salt forming reaction on a compound shown in a formula 2 and X as follows;
；
wherein X is as claimed in claim 1.
4. The method for preparing a compound represented by formula 5 according to claim 3, wherein the organic solvent is one or more of halogenated hydrocarbon solvents, nitrile solvents, ketone solvents, ester solvents and alcohol solvents;
and/or, the sulfuric acid is added in the form of sulfuric acid aqueous solution;
and/or the molar ratio of X to the compound shown as the formula 2 is 1:1-6:1;
and/or the volume-mass ratio of the organic solvent to the compound shown as the formula 2 is 1-50 mL/g;
and/or the temperature of the salification reaction is-20-20 ℃.
5. The method for producing a compound of formula 5 according to claim 4, wherein the halogenated hydrocarbon solvent is methylene chloride; the nitrile solvent is acetonitrile; the ketone solvent is acetone; the ester solvent is ethyl acetate; the alcohol solvent is one or more of methanol, ethanol, propanol and butanol;
and/or the sulfuric acid aqueous solution is 80-98% sulfuric acid aqueous solution by mass fraction;
and/or the volume-mass ratio of the organic solvent to the compound shown as the formula 2 is 1-20 mL/g;
and/or the temperature of the salification reaction is-10-10 ℃.
6. The process for producing a compound of formula 5 according to claim 4,
the organic solvent is an alcohol solvent;
and/or the sulfuric acid aqueous solution is 98% sulfuric acid aqueous solution by mass fraction;
and/or the volume-mass ratio of the organic solvent to the compound shown as the formula 2 is 5-20 mL/g;
and/or the temperature of the salification reaction is 0-10 ℃.
7. The method for producing a compound of formula 5 according to claim 6,
the alcohol solvent is ethanol;
and/or the volume-mass ratio of the organic solvent to the compound shown in the formula 2 is 15-20 mL/g.
8. A process for preparing a compound of formula 5 as claimed in claim 3, further comprising the steps of:
(1) In an organic solvent and water, in the presence of benzotriazole, carrying out an addition reaction on a compound shown as a formula 1 and glyoxal to obtain a reaction liquid 1;
(2) Carrying out reduction reaction on the reaction liquid 1 in the step (1) in the presence of a reducing agent;
。
9. the method for producing a compound represented by formula 5 according to claim 8, wherein in the step (1), the organic solvent is one or more of an alcohol solvent, an ether solvent, an ester solvent, a nitrile solvent, a halogenated hydrocarbon solvent, a ketone solvent and an aromatic hydrocarbon solvent;
and/or, in step (1), said water and said glyoxal are added in the form of an aqueous glyoxal solution;
and/or, in the step (1), the molar ratio of glyoxal to the compound shown as the formula 1 is 2:1-8:1;
and/or, in the step (1), the molar ratio of the benzotriazole to the compound shown as the formula 1 is 2:1-8:1;
and/or in the step (1), the volume-mass ratio of the organic solvent to the compound shown as the formula 1 is 3-30 mL/g;
and/or, in the step (1), the temperature of the addition reaction is from-20 ℃ to the reflux temperature of the organic solvent under normal pressure;
and/or in the step (2), the reducing agent is one or more of sodium borohydride, lithium aluminum hydride, hydrogen, hydrazine hydrate, ammonium formate, formic acid and triethylamine formic acid azeotrope;
and/or, in the step (2), the molar ratio of the reducing agent to the compound shown as the formula 1 in the step (1) is 2:1-20:1;
and/or, in the step (2), the temperature of the reduction reaction is 0 ℃ to the reflux temperature of the organic solvent under normal pressure.
10. The method for producing a compound of formula 5 according to claim 9, wherein in step (1), the alcoholic solvent is one or more of ethanol, methanol and isopropanol; the ether solvent is methyl tertiary butyl ether; the ester solvent is ethyl acetate and/or isopropyl acetate; the nitrile solvent is acetonitrile; the halogenated hydrocarbon solvent is dichloromethane; the ketone solvent is acetone; the aromatic hydrocarbon solvent is toluene and/or xylene;
and/or, in the step (1), the glyoxal aqueous solution is glyoxal aqueous solution with the mass fraction of 10% -40%;
and/or, in the step (1), the molar ratio of glyoxal to the compound shown as the formula 1 is 2:1-3:1;
and/or, in the step (1), the molar ratio of the benzotriazole to the compound shown as the formula 1 is 2:1-3:1;
and/or in the step (1), the volume-mass ratio of the organic solvent to the compound shown as the formula 1 is 3-9 mL/g;
and/or, in the step (1), the temperature of the addition reaction is 0-20 ℃;
and/or, in the step (2), the reducing agent is sodium borohydride;
and/or, in the step (2), the molar ratio of the reducing agent to the compound shown as the formula 1 in the step (1) is 2:1-4:1;
and/or, in the step (2), the temperature of the reduction reaction is 0-20 ℃.
11. The method for producing a compound of formula 5 according to claim 9, wherein in step (1), the organic solvent is an alcohol solvent;
and/or in the step (1), the volume-mass ratio of the organic solvent to the compound shown as the formula 1 is 3-6 mL/g.
12. The method for producing a compound of formula 5 according to claim 11, wherein in step (1), the alcohol solvent is ethanol.
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| US20060217548A1 (en) * | 2003-06-13 | 2006-09-28 | Boschetti Frederic | Method of preparing cis-8b-methyldecahydro-2a,4a,6a,8a-tetraazacyclopenta[fg] acenaphthylene, cis-decahydro-2a,4a,6a,8a-tetraazacyclopenta[fg] acenaphthylene, cyclene and functionalised cyclenes |
| CN107915691A (en) * | 2017-11-14 | 2018-04-17 | 上海凌凯医药科技有限公司 | A kind of synthetic method of the cycleanine based on efficient green low cost |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20060217548A1 (en) * | 2003-06-13 | 2006-09-28 | Boschetti Frederic | Method of preparing cis-8b-methyldecahydro-2a,4a,6a,8a-tetraazacyclopenta[fg] acenaphthylene, cis-decahydro-2a,4a,6a,8a-tetraazacyclopenta[fg] acenaphthylene, cyclene and functionalised cyclenes |
| CN107915691A (en) * | 2017-11-14 | 2018-04-17 | 上海凌凯医药科技有限公司 | A kind of synthetic method of the cycleanine based on efficient green low cost |
Non-Patent Citations (1)
| Title |
|---|
| Michael and Irene Ash.《Handbook of Corrosion Inhibitors Second Edition》.Synapse Information Resources, Inc.,2011,第190页. * |
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Address after: No.8, yongjiao Road, Huangyan Economic Development Zone, Taizhou City, Zhejiang Province Patentee after: LIANHE CHEMICAL TECHNOLOGY Co.,Ltd. Country or region after: China Patentee after: Lianhua Angjian (Zhejiang) Pharmaceutical Co.,Ltd. Patentee after: LIANHE CHEMICAL TECHNOLOGY (SHANGHAI) Co.,Ltd. Address before: No.8, yongjiao Road, Huangyan Economic Development Zone, Taizhou City, Zhejiang Province Patentee before: LIANHE CHEMICAL TECHNOLOGY Co.,Ltd. Country or region before: China Patentee before: LIANHE CHEMICAL TECHNOLOGY (TAIZHOU) Co.,Ltd. Patentee before: LIANHE CHEMICAL TECHNOLOGY (SHANGHAI) Co.,Ltd. |