CN113072514A - Preparation method of cycleanine and intermediate thereof - Google Patents
Preparation method of cycleanine and intermediate thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 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 abstract description 6
- 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 abstract description 6
- 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 abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 86
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 58
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical group OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 42
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical group OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 38
- 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
- 238000006722 reduction reaction Methods 0.000 claims abstract description 22
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 66
- 239000002904 solvent Substances 0.000 claims description 63
- 238000000034 method Methods 0.000 claims description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 42
- 239000003960 organic solvent Substances 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 238000001914 filtration Methods 0.000 claims description 35
- 239000007864 aqueous solution Substances 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 22
- 229940015043 glyoxal Drugs 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 17
- 238000010992 reflux Methods 0.000 claims description 16
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-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
- 238000011085 pressure filtration Methods 0.000 claims description 12
- 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 9
- 238000006386 neutralization reaction 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
- 238000007259 addition reaction Methods 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 150000008282 halocarbons Chemical class 0.000 claims description 8
- 150000002825 nitriles Chemical class 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 7
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 239000012279 sodium borohydride Substances 0.000 claims description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000005456 alcohol based solvent Substances 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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 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
- 239000003759 ester based solvent Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 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
- 239000005453 ketone based solvent Substances 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- 150000003016 phosphoric acids Chemical class 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
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 11
- 238000000746 purification Methods 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- QBPPRVHXOZRESW-UHFFFAOYSA-N 1,4,7,10-tetraazacyclododecane Chemical compound C1CNCCNCCNCCN1 QBPPRVHXOZRESW-UHFFFAOYSA-N 0.000 description 17
- 239000012065 filter cake Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 229960001124 trientine Drugs 0.000 description 7
- 230000005494 condensation Effects 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
- 238000009833 condensation Methods 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
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 238000010626 work up procedure Methods 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
- 230000007547 defect Effects 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000007296 Stetter synthesis reaction Methods 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- 230000003321 amplification Effects 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
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910021645 metal ion Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 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
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000006227 byproduct Substances 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
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000007796 conventional method Methods 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
- 229940043237 diethanolamine Drugs 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
- 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
- 238000013421 nuclear magnetic resonance imaging 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
- 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
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000006049 ring expansion reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000007070 tosylation reaction Methods 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of cycleanine 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 a reduction reaction on a compound shown as a formula 3 and hydrazine hydrate as shown in the specification; 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 has the advantages of 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, and particularly relates to a preparation method of cycleanine and an intermediate thereof.
Background
Cyclen (1,4,7, 10-tetraazadodecane, Cyclen), a white or nearly white crystalline powder chemical. Molecular formula C8H20N4And the molecular weight is 172.28. Is an important intermediate for synthesizing the therapeutic drugs of the diagnostic kit. The cyclen and the derivatives thereof are used for removing stones in human bodies, and particularly show extremely important application values in the aspects of manufacturing contrast agents of medical imaging technologies such as nuclear Magnetic Resonance Imaging (MRI), X-ray CT, ultrasonic imaging and the like and radiopharmaceutical treatment of malignant tumors. The complex can form a stable complex with ions as a precursor of a macrocyclic chelating agent for synthesizing metal ions, particularly paramagnetic metal ions such as a complex formed with gadolinium ions, is applied to the field of medical diagnosis, does not have high toxicity caused by free ions, and has the safety characteristic. At present, the aging is more and more serious in the world, the demand of the cyclen is more and more, 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.
At present, the chemical synthesis methods of cyclen mainly comprise 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 the synthesis of macrocyclic polyamines was proposed by Stetter and Max in 1957 (Stetter, H.; Marx, J.chem.Brit.1957,607,59), which uses a condensation cyclization of a di-p-toluenesulfonamide derivative of ethylenediamine diacetoxy chloride with ethylenediamine under highly dilute conditions (about 0.001mol/L), followed by reduction and deprotection to give the desired product. The raw materials required by the method are not easy to obtain, and the method is not suitable for industrial mass preparation due to the ring closure under the high dilution condition, the reaction yield is not high, the productivity is limited, and the method is rarely adopted at present.
Richman-Atkins synthesis method
For many years, people prefer to use the Richman-Atkins method (Richman, J.E.; Atkins, T.J.J.Am.chem.Soc.1974,96,2268) to synthesize cyclen, which has become the classic method for preparing cyclen. The method uses diethyl triamine and diethanol amine to respectively prepare cycleanine through 5 steps of tosylation, salification, ring closing, protecting group removal, alkalization extraction and the like. The method has high yield and large synthesis amount, and is one of the current main ways for preparing cyclen in a laboratory. However, the method has many experimental steps, large reagent consumption for protection and deprotection, low atom utilization rate and inconvenient operation, and is not an ideal industrial synthetic route.
Weisman synthesis method
The above-described Richman-Atkins synthesis requires removal of the four p-toluenesulfonyl groups during synthesis, which is not consistent with atom economy guidelines. Having noticed this drawback, Weisman et al proposed a new method for the synthesis of cyclen (Weisman, g.r.org.chem.1997,62,4548). Namely, dithiooxamide and triethylenetetramine directly react to obtain tricyclic diamidine, and then diisobutylaluminum hydride (DIBALH) is used for carrying out double reduction to obtain cycleanine after ring expansion, wherein the total yield is 67%.
The method 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. The solvent is required in a proper amount as compared with the Richman-Atkins method, which has disadvantages in that dithiooxamide as a starting material is expensive, hydrogen sulfide is generated as a by-product in the reaction, DIBALH used in the reduction step is expensive and sensitive to moisture, and the operation requires extra care and is limited by the above factors, and which is suitable for synthesis of only a small amount.
Condensation of glyoxal
The glyoxal condensation process is a new process developed in recent years. The condensation of glyoxal water solution and triethylenetetramine is adopted to prepare cyclen (Hervre, G.tetrahedron Lett.1999,40,2517), and the common points of the two are that one or a plurality of rigid intermediates which are isomers each other are firstly obtained, and cyclen is then obtained through cyclization and deprotection steps. The method has the advantages of easily available raw materials, low cost, mild reaction conditions and simpler product purification.
The biggest problem of the route is that during the further ring closing process of the rigid intermediate and dibromoethane, the ring forming reaction is competitive with the reaction of dibromoethane and tertiary amine to form quaternary ammonium salt, and the yield is low. The amplification effect in the industrial production process is more difficult to control for the side reaction, so the strategy of forming the rigid intermediate by using the triethylenetetramine as the starting material is not suitable for the amplification production.
Diethyl oxalate synthesis method
The method has less research, and the product is obtained by adopting triethylene tetramine and diethyl oxalate to condense and close a ring (Wei, J. -F.chem.J.Chin.Univ.1997,18,658) and then reducing with diborane. The condensation and ring-closing reaction of triethylenetetramine and diethyl oxalate also has the defects that the reaction needs to be carried out at a relatively dilute concentration and is not suitable for industrial production.
The above routes have great defects in raw materials or processes, and bring certain difficulties to the industrial production of cyclen.
Disclosure of Invention
The invention aims to overcome the defect of single type of the existing cyclocyclen synthesis route, and provides a preparation method of cyclocyclen and an intermediate thereof. The preparation method has the advantages of low cost, simple and convenient operation, easy purification of intermediates and products, high yield and purity, and suitability for industrial production.
The present invention solves the above-mentioned problems by the following technical solutions.
The invention provides a preparation method of a compound shown as a formula 4, which comprises the following steps: in water, carrying out a reduction reaction on a compound shown as a formula 3 and hydrazine hydrate as shown in the specification;
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 hydrazine hydrate aqueous solution. The hydrazine hydrate aqueous solution can be a hydrazine hydrate aqueous solution with the mass fraction which is conventional in the field, preferably a hydrazine hydrate aqueous solution with the mass fraction of 50-80%, for example a hydrazine hydrate aqueous solution with the mass fraction of 50% or 80%.
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 molar ratio which is conventional in the field, and is preferably 3:1-5:1, such as 3:1 or 5: 1.
In the preparation method of the compound represented by the 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 method of the compound represented by formula 4, the progress of the reduction reaction can be monitored by means conventional in the art (such as TLC, HPLC, GC or NMR, preferably GC), and the time of the reduction reaction is preferably 12 to 96 hours, more preferably 12 to 30 hours, such as 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 a salt forming reaction on a compound shown as a formula 2 and X as shown in the specification;
wherein n and X are as defined above.
In the salt forming reaction, the organic solvent may be an organic solvent which is conventional in the art, preferably one or more of halogenated hydrocarbon solvents, nitrile solvents, ketone solvents, ester solvents and alcohol solvents, and more preferably an alcohol solvent. The halogenated hydrocarbon solvent is preferably dichloromethane. 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, and more preferably ethanol.
In the salt-forming reaction, when X is phosphoric acid, the phosphoric acid can be added in the form of a phosphoric acid aqueous solution. The phosphoric acid aqueous solution can be phosphoric acid aqueous solution with mass fraction which is conventional in the field, preferably phosphoric acid aqueous solution with mass fraction of 65-85%, and more preferably phosphoric acid aqueous solution with mass fraction of 85%.
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 sulfuric acid aqueous solution can be a sulfuric acid aqueous solution with a mass fraction which is conventional in the field, preferably an 80-98% sulfuric acid aqueous solution, and more preferably a 98% sulfuric acid aqueous solution.
In the salt-forming reaction, the molar ratio of the X to the compound represented by the formula 2 can be a molar ratio which is conventional in the art, and is preferably 1:1 to 6:1, such as 2.15:1, 2.37:1 or 6: 1.
In the salt-forming reaction, the volume-to-mass ratio of the organic solvent to the compound represented by the formula 2 can be a volume-to-mass ratio conventional in the art, and is preferably 1 to 50mL/g, more preferably 1 to 20mL/g, further preferably 5 to 20mL/g, further preferably 15 to 20mL/g, for example 17.86 mL/g.
In the salt-forming reaction, the temperature of the salt-forming reaction may be a temperature conventional in the art, and is preferably-20 to 20 ℃, more preferably-10 to 10 ℃, further preferably 0 to 10 ℃, for example 0 ℃.
In the salt-forming reaction, the progress of the salt-forming reaction can be monitored by means conventional in the art (e.g., TLC, HPLC, GC, or NMR, preferably GC), and the time of the salt-forming reaction is preferably 5 to 40 hours, more preferably 5 to 10 hours, e.g., 5 hours.
The work-up of the salt-forming reaction may be a work-up conventional in the art, which comprises the following steps: and filtering the reaction solution, washing a filter cake, and drying. The solvent for washing 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) carrying out addition reaction on a compound shown as a formula 1 and glyoxal in the presence of benzotriazole by using an organic solvent and water to obtain a reaction solution 1;
(2) in the presence of a reducing agent, carrying out reduction reaction on the reaction solution 1 in the step (1);
in the step (1), the organic solvent may be an organic solvent conventional in the art, preferably 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 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 tert-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 dichloromethane. The ketone solvent is preferably acetone. The aromatic hydrocarbon solvent is preferably toluene and/or xylene.
In the step (1), the water and the glyoxal may be added in the form of aqueous glyoxal solution, which may be aqueous glyoxal solution with a mass fraction conventional in the art, preferably aqueous glyoxal solution with a mass fraction of 10% -40%, for example, aqueous glyoxal solution with a mass fraction of 40%.
In step (1), the molar ratio of the glyoxal 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 the step (1), the molar ratio of the benzotriazole to the compound shown in formula 1 may be a molar ratio which is conventional in the art, and is preferably 2:1-8:1, more preferably 2:1-3:1, such as 2: 1.
In the step (1), the volume-to-mass ratio of the organic solvent to the compound represented by the formula 1 may be a volume-to-mass ratio conventionally used in the art, and is preferably 3 to 30mL/g, more preferably 3 to 9mL/g, further preferably 3 to 6mL/g, for example 4 mL/g.
In step (1), the temperature of the addition reaction may be a temperature conventional in the art, preferably from-20 ℃ to the reflux temperature of the organic solvent under normal pressure, more preferably from 0 to 20 ℃, for example, 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), preferably for a period of 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 gas, 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 represented by 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 the step (2), the temperature of the reduction reaction may be a reaction temperature conventional in the art, preferably 0 ℃ to the reflux temperature of the organic solvent under normal pressure, more preferably 0 to 20 ℃, for example, 0 ℃.
In step (2), the reduction may be monitored by means conventional in the art (e.g. TLC, HPLC, GC or NMR, preferably GC), preferably for a period of 3 to 72 hours, more preferably 3 to 12 hours, for example 3 hours.
The work-up operation of the reduction reaction may be a work-up operation conventional in the art, comprising the following steps: removing organic solvent, removing water, filtering, and concentrating the filtrate. The method of removing the organic solvent is preferably concentration, more preferably concentration under reduced pressure/atmospheric pressure. Before the organic solvent is removed, a filtration operation is preferably further included. The water removal is preferably carried out by adding an organic solvent. The water diversion operation can be the operation conventional in the field, and the water diversion under the normal pressure reflux is preferred. 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 temperature reduction step, wherein the temperature reduction is preferably carried out to 20-30 ℃, for example 20 ℃. Preferably, before concentrating the filtrate, the operation of washing the filter cake can be further included. The solvent for washing is preferably an aromatic hydrocarbon solvent such as toluene. The number 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) preparing a compound shown in a formula 4 according to any one method;
(2) carrying out neutralization reaction on the compound shown in the formula 4 obtained in the step (1) and alkali as shown in the specification;
wherein n and X are as defined above;
in the preparation method of the compound shown in the formula 5, in the step (1), the reduction reaction conditions and operation are the same as those of the reaction.
In the preparation method of the compound represented by the formula 5, in the step (2), the base can be a base conventional in the art, preferably an alkali metal hydroxide, and 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 represented by the formula 5, in the step (2), the post-treatment of the neutralization reaction may be a post-treatment conventional in the art, and comprises the following steps: concentrating the reaction solution, adding a solvent to extract a concentrate, filtering an organic phase, concentrating, and recrystallizing to obtain the compound. The concentration is preferably carried out under reduced pressure. 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) carrying out addition reaction on a compound shown as a formula 1 and glyoxal in the presence of benzotriazole by using an organic solvent and water to obtain a reaction solution 1;
(2) the reaction solution 1 obtained in the step (1) is subjected to a reduction reaction in the presence of a reducing agent, and the post-treatment comprises 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 as the formula 2, in the step (1), the conditions and 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 reduction reaction conditions and operation are the same as those of the reaction.
In the preparation method of the compound represented by the formula 2, in the step (2), the method for removing the organic solvent may be a method conventional in the art, and preferably concentration under reduced pressure or concentration under normal pressure is performed.
In the preparation method of the compound represented by the formula 2, before removing the organic solvent in the step (2), a filtration operation is preferably further included, and the filtration conditions and methods may be those conventional in the art, such as reduced pressure filtration or atmospheric 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 preferably performs water diversion under reduced pressure reflux or water diversion under normal pressure reflux, and more preferably performs water diversion under normal pressure reflux. The organic solvent used for the water separation is preferably an aromatic hydrocarbon solvent, and more preferably toluene.
In the preparation method of the compound shown as 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 preparation method of the compound represented by the formula 2, in the step (2), the filtration operation may be an operation conventional in the art, such as reduced pressure filtration or atmospheric pressure filtration.
In the preparation method of the compound shown in the formula 2, in the step (2), after the filtration is finished, the washing operation can be further included. The solvent for washing is preferably an aromatic hydrocarbon solvent such as toluene. The number of washing is preferably 1 to 2.
In the preparation method of the compound represented by the formula 2, in the step (2), the concentration operation may be an operation conventional in the art, for example, concentration under reduced pressure or concentration under normal pressure.
The invention also provides a purification method of the compound shown as the formula 2, which comprises the following steps: a mixture comprising a 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 method for purifying the compound represented by formula 2, the method for removing the organic solvent may be a method conventional in the art, and preferably concentration under reduced pressure or concentration under normal pressure.
In the method for purifying the compound represented by formula 2, before removing the organic solvent, a filtration operation is preferably further included, and the filtration conditions and method may be those conventional in the art, such as reduced pressure filtration or atmospheric pressure filtration.
In the purification method of the compound shown in the formula 2, the water diversion operation can be a conventional operation in the field, and preferably carries out water diversion under reduced pressure reflux or water diversion under normal pressure reflux, and more preferably carries out water diversion under normal pressure reflux. The organic solvent used for the water separation is preferably an aromatic hydrocarbon solvent, and more preferably toluene.
In the purification method of 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 method for purifying the compound represented by the formula 2, the filtration operation may be an operation conventional in the art, such as reduced pressure filtration or atmospheric pressure filtration.
In the method for purifying the compound represented by the formula 2, after the filtration is finished, preferably, a washing operation may be further included. The solvent for washing is preferably an aromatic hydrocarbon solvent such as toluene. The number of washing is preferably 1 to 2.
In the purification method of the compound represented by the formula 2, the concentration operation may be an operation conventional in the art, such as concentration under reduced pressure or concentration under normal pressure.
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 to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
In the present invention, "° c" means "degrees celsius", unless otherwise specified; "h" means "hour".
In the present invention, the 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 positive progress effects of the invention are as follows: the preparation method has the advantages of 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 the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
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 dropwise added at 0 ℃, the mixture is stirred for 3 hours at 0 ℃, and the reaction is controlled to be qualified. 52 g of sodium borohydride was 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 for normal-pressure reflux water separation, completely removing the water, cooling to 20 ℃, filtering to remove insoluble solid benzotriazole (used for recovery, the recovery rate is 92%), washing the filter cake once with 100mL of toluene, combining the filtrates, and concentrating the filtrate under reduced pressure until no obvious fraction is distilled off to obtain the compound of the formula 2, wherein the compound of the formula 2 is 100 g of pale yellow oily substance, the yield is 75%, and the content is about 70%.1H NMR(CDCl3,400MHz):3.087(s,2H),2.959-2.875(m,8H),2.635-2.487(m,8H).13C NMR(CDCl3,125.8MHz):77.43,51.04,50.26.GC-MS:194.
Example 2
56 g of the compound of the formula 2 (in 100% purity) are dissolved in 1000mL of ethanol, cooled to 0 ℃ and 68.6 g of 98% sulfuric acid are added dropwise, and the mixture is stirred at 0 ℃ for 5 hours. Filtering, washing a filter cake by using ethanol, and drying the filter cake to obtain 107 g of the compound shown in the formula 3-1 with the yield of 95%. Purity of compound 3-1 is not less than 96%, total nitrogen: 14.45 percent.
Example 3
56 g of the compound of the formula 2 (in 100% purity) are dissolved in 1000mL of ethanol, 173 g of 98% sulfuric acid are added dropwise, cooling to 0 ℃ and stirring for 5 hours at 0 ℃. Filtering, washing a filter cake by using ethanol, and drying the filter cake to obtain 108 g of the compound shown in the formula 3-1 with the yield of 95%.
Example 4
56 g of the compound of the formula 2 (in 100% purity) are dissolved in 1000mL of ethanol, cooled to 0 ℃ and 72 g of 85% phosphoric acid are added dropwise, and the mixture is 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 shown in the formula 3-2, wherein the yield is 95%, the purity of the compound 3-2 is not less than 96%, and the total nitrogen: 17.50 percent.
Example 5
100 g of a compound of formula 3-1 (100% pure) in waterDissolving in 80 g of 80% hydrazine hydrate, heating to 90 ℃, and keeping the temperature for 12 hours. After the completion of the neutralization reaction, 31 g of sodium hydroxide was added, followed by removing the aqueous phase by concentration under reduced pressure, and 200mL of toluene was added to extract the concentrated residue. Filtering to remove insoluble substances, concentrating the filtrate, adding 200mL of toluene for recrystallization, filtering to remove mother liquor, and drying the filter cake to obtain 33 g of white cyclen product, wherein the yield is 75% and the purity is more than 99.5%.1H NMR(CDCl3,400MHz):2.485-2.435(d,16H),1.832(s,4H).13C NMR(CDCl3,125.8MHz):45.9.GC-MS:172.
Example 6
100 g of the compound of formula 3-1 (in 100% purity) was dissolved in 128 g of 50% hydrazine hydrate, heated to 90 ℃ and incubated for 12 hours. After the completion of the neutralization reaction, 31 g of sodium hydroxide was added, followed by removing the aqueous phase by concentration under reduced pressure, and 200mL of toluene was added to extract the concentrated residue. Filtering to remove insoluble substances, concentrating the filtrate, adding 200mL of toluene for recrystallization, filtering to remove mother liquor, and drying the filter cake to obtain 35 g of white cyclen product, wherein 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 (in 100% purity) was dissolved in 48 g of 80% hydrazine hydrate, heated to 90 ℃ and incubated for 12 hours. After the completion of the neutralization reaction, 31 g of sodium hydroxide was added, followed by removing the aqueous phase by concentration under reduced pressure, and 200mL of toluene was added to extract the concentrated residue. Filtering to remove insoluble substances, concentrating the filtrate, adding 200mL of toluene for recrystallization, filtering to remove mother liquor, and drying the filter cake to obtain 32 g of white cyclen product, wherein the yield is 73% and the purity is more than 99.5%.
Example 8
100 g of the compound of formula 3-2 (in 100% purity) are dissolved in 80 g of 80% hydrazine hydrate, the temperature is raised to 90 ℃ and the incubation is carried out for 12 hours. After the end of the neutralization reaction, 40 g of sodium hydroxide were added, followed by removal of the aqueous phase by concentration under reduced pressure, and extraction of the residue by addition of 200mL of toluene. Filtering to remove insoluble substances, concentrating the filtrate, adding 200mL of toluene for recrystallization, filtering to remove mother liquor, and drying the filter cake to obtain 29 g of white cyclen product, wherein the yield is 55%, and the purity is more than 99.5%.
Comparative example 1
87 g of the starting compound (100% purity) are dissolved in 80 g of 80% hydrazine hydrate, the temperature is raised to 90 ℃ and the incubation is carried out for 12 hours. After the completion of the neutralization reaction, 31 g of sodium hydroxide was added, followed by removing the aqueous phase by concentration under reduced pressure, and 200mL of toluene was added to extract the concentrated residue. Filtering to remove insoluble substances, concentrating the filtrate, adding 200mL of toluene for recrystallization, filtering to remove mother liquor, and drying the filter cake to obtain 19 g of white cyclen product with the yield of 43%.
Comparative example 2
The following compound 2 was synthesized with reference to the method in patent US 7659393B.
10g (68.4mmol) of triethylenetetramine and 16.3g (136.7mmol) of benzotriazole are dissolved in 200mL of water, cooled to 2 ℃ and 80mL of a methanolic glyoxal solution are slowly added dropwise thereto (19.86 g (136.7mmol) of an aqueous glyoxal solution are added to 80mL of methanol). After the dropwise addition, the mixture was warmed to room temperature and stirred for 4 hours. Thereafter, 5.18g (136.7mmol) of sodium borohydride was added in portions, and stirred at room temperature for 2 hours. After 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 as a yellow oil (9g, yield 68%, content: about 70%).
In the actual operation process, the extraction process is easy to generate emulsification phenomenon, difficult to stratify, large in product loss, complex in operation, long in time consumption, and difficult to recycle benzotriazole.
Claims (11)
1. A preparation method of a compound shown as a formula 4 is characterized by comprising the following steps: in water, carrying out a reduction reaction on a compound shown as a formula 3 and hydrazine hydrate as shown in the specification;
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.
2. The process according to claim 1 for preparing a compound represented by the formula 4,
x is sulfuric acid;
and/or the water and the hydrazine hydrate are added in the form of hydrazine hydrate aqueous solution, and the hydrazine hydrate aqueous solution is preferably hydrazine hydrate aqueous solution with the mass fraction of 50-80%;
and/or the molar ratio of the hydrazine hydrate to the compound shown in the formula 3 is 3:1-5: 1;
and/or the temperature of the reduction reaction is 60-100 ℃, preferably 80-90 ℃.
3. The method of claim 1 or 2, further comprising the steps of: in an organic solvent, carrying out a salt forming reaction on a compound shown as a formula 2 and X as shown in the specification;
wherein X is as defined in claim 1 or 2.
4. The method for preparing the compound represented by the formula 4 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, preferably alcohol solvents; the halogenated hydrocarbon solvent is preferably dichloromethane; 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, and more preferably ethanol;
and/or when X is phosphoric acid, adding the phosphoric acid in the form of a phosphoric acid aqueous solution, wherein the phosphoric acid aqueous solution is preferably a phosphoric acid aqueous solution with the mass fraction of 65-85%, and more preferably a phosphoric acid aqueous solution with the mass fraction of 85%;
and/or, when X is sulfuric acid, the sulfuric acid is added in the form of an aqueous sulfuric acid solution; the sulfuric acid aqueous solution is preferably 80-98% in mass fraction, and is more preferably 98% in mass fraction;
and/or the molar ratio of the X to the compound shown in the formula 2 is 1:1-6: 1;
and/or the volume-to-mass ratio of the organic solvent to the compound shown in the formula 2 is 1-50mL/g, preferably 1-20mL/g, more preferably 5-20mL/g, and even more preferably 15-20 mL/g;
and/or the temperature of the salt forming reaction is-20-20 ℃, preferably-10-10 ℃, and further preferably 0-10 ℃.
5. The method of claim 3, further comprising the steps of:
(1) carrying out addition reaction on a compound shown as a formula 1 and glyoxal in the presence of benzotriazole by using an organic solvent and water to obtain a reaction solution 1;
(2) in the presence of a reducing agent, carrying out reduction reaction on the reaction solution 1 in the step (1);
6. the method according to claim 5, wherein in the step (1), the organic solvent is one or more selected from the group consisting 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, 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 tert-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 dichloromethane; the ketone solvent is preferably acetone; the aromatic hydrocarbon solvent is preferably toluene and/or xylene;
and/or, in step (1), said water and said glyoxal are added in the form of an aqueous glyoxal solution; the glyoxal water solution with the mass fraction of 10% -40% is preferably selected;
and/or in the step (1), the molar ratio of the glyoxal to the compound shown in the formula 1 is 2:1-8:1, preferably 2:1-3: 1;
and/or in the step (1), the molar ratio of the benzotriazole to the compound shown in the formula 1 is 2:1-8:1, preferably 2:1-3: 1;
and/or, in the step (1), the volume-to-mass ratio of the organic solvent to the compound shown in the formula 1 is 3-30mL/g, preferably 3-9mL/g, and more preferably 3-6 mL/g;
and/or, in the step (1), the temperature of the addition reaction is-20 ℃ to the reflux temperature of the organic solvent under normal pressure, and the reflux temperature is preferably 0-20 ℃;
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, preferably sodium borohydride;
and/or, in the step (2), the molar ratio of the reducing agent to the compound shown in the formula 1 in the step (1) is 2:1-20:1, preferably 2:1-4: 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, preferably 0-20 ℃.
7. A preparation method of a compound shown as a formula 5 comprises the following steps:
(1) preparing a compound shown in the formula 4 according to the preparation method of any one of claims 1 to 6;
(2) carrying out neutralization reaction on the compound shown in the formula 4 obtained in the step (1) and alkali as shown in the specification;
wherein n and X are as defined in claim 1 or 2.
8. A preparation method of a compound shown as a formula 2 comprises the following steps:
(1) carrying out addition reaction on a compound shown as a formula 1 and glyoxal in the presence of benzotriazole by using an organic solvent and water to obtain a reaction solution 1;
(2) the reaction solution 1 obtained in the step (1) is subjected to a reduction reaction in the presence of a reducing agent, and the post-treatment comprises the steps of: removing organic solvent, removing water, filtering, and concentrating; the water removal is water diversion water removal;
9. the method according to claim 8, wherein the step (2) of removing the organic solvent is vacuum concentration or atmospheric concentration;
and/or, in the step (2), before removing the organic solvent, a filtering operation is further included; the filtration is preferably reduced pressure filtration or normal pressure filtration;
and/or in the step (2), the water diversion is reduced pressure reflux water diversion or normal pressure reflux water diversion, preferably normal pressure reflux water diversion;
and/or, in the step (2), the organic solvent used for water separation is an aromatic hydrocarbon solvent, preferably toluene;
and/or, in the step (2), after the water removal is finished, further comprising a cooling step, wherein the cooling is preferably cooled to 20-30 ℃;
and/or, in the step (2), the filtration is reduced pressure filtration or normal pressure filtration;
and/or, in the step (2), after the filtration is finished, further comprising a washing operation; the washed solvent is preferably an aromatic hydrocarbon solvent; the number of washing is preferably 1 to 2;
and/or, in the step (2), the concentration is reduced pressure concentration or normal pressure concentration.
10. A method for purifying a compound represented by formula 2, comprising the steps of: a mixture comprising a 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;
11. a compound shown as a formula 4-1 or a formula 4-2,
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114436984A (en) * | 2022-01-05 | 2022-05-06 | 上海凌凯医药科技有限公司 | Preparation method of cycleanine |
| CN114436984B (en) * | 2022-01-05 | 2024-02-23 | 上海凌凯医药科技有限公司 | Preparation method of Xuancyclic vine |
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