CN113501797A - Preparation method of exterior nadic anhydride - Google Patents
Preparation method of exterior nadic anhydride Download PDFInfo
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- CN113501797A CN113501797A CN202110934986.XA CN202110934986A CN113501797A CN 113501797 A CN113501797 A CN 113501797A CN 202110934986 A CN202110934986 A CN 202110934986A CN 113501797 A CN113501797 A CN 113501797A
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- nadic anhydride
- anhydride
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- KNDQHSIWLOJIGP-UMRXKNAASA-N (3ar,4s,7r,7as)-rel-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1,3-dione Chemical compound O=C1OC(=O)[C@@H]2[C@H]1[C@]1([H])C=C[C@@]2([H])C1 KNDQHSIWLOJIGP-UMRXKNAASA-N 0.000 title description 21
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims abstract description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 30
- KNDQHSIWLOJIGP-RNGGSSJXSA-N (3ar,4r,7s,7as)-rel-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1,3-dione Chemical compound C1[C@@H]2[C@@H]3C(=O)OC(=O)[C@@H]3[C@H]1C=C2 KNDQHSIWLOJIGP-RNGGSSJXSA-N 0.000 claims abstract description 27
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 15
- 239000007788 liquid Substances 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 3
- 238000010791 quenching Methods 0.000 claims abstract description 3
- 230000000171 quenching effect Effects 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000011112 process operation Methods 0.000 abstract description 2
- 239000000126 substance Substances 0.000 description 21
- 239000000047 product Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 238000001035 drying Methods 0.000 description 12
- 238000005698 Diels-Alder reaction Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 8
- CEIJFEGBUDEYSX-FZDBZEDMSA-N tandospirone Chemical compound O=C([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C1=O)N1CCCCN(CC1)CCN1C1=NC=CC=N1 CEIJFEGBUDEYSX-FZDBZEDMSA-N 0.000 description 7
- 229950000505 tandospirone Drugs 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 239000000178 monomer Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- HECLRDQVFMWTQS-RGOKHQFPSA-N 1755-01-7 Chemical compound C1[C@H]2[C@@H]3CC=C[C@@H]3[C@@H]1C=C2 HECLRDQVFMWTQS-RGOKHQFPSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 239000011968 lewis acid catalyst Substances 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- DVWQNBIUTWDZMW-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalen-2-ol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=CC=CC2=C1 DVWQNBIUTWDZMW-UHFFFAOYSA-N 0.000 description 1
- FWKCXFPQSXNCBW-UHFFFAOYSA-N 2,2-diethylpropanedioyl dichloride Chemical compound CCC(CC)(C(Cl)=O)C(Cl)=O FWKCXFPQSXNCBW-UHFFFAOYSA-N 0.000 description 1
- ATGFTMUSEPZNJD-UHFFFAOYSA-N 2,6-diphenylphenol Chemical compound OC1=C(C=2C=CC=CC=2)C=CC=C1C1=CC=CC=C1 ATGFTMUSEPZNJD-UHFFFAOYSA-N 0.000 description 1
- -1 4- (2-pyrimidinyl) -1-piperazinyl Chemical group 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- STVVMTBJNDTZBF-VIFPVBQESA-N L-phenylalaninol Chemical compound OC[C@@H](N)CC1=CC=CC=C1 STVVMTBJNDTZBF-VIFPVBQESA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CKRHKYHOTKICCR-UHFFFAOYSA-K aluminum;2,6-diphenylphenolate Chemical compound [Al+3].[O-]C1=C(C=2C=CC=CC=2)C=CC=C1C1=CC=CC=C1.[O-]C1=C(C=2C=CC=CC=2)C=CC=C1C1=CC=CC=C1.[O-]C1=C(C=2C=CC=CC=2)C=CC=C1C1=CC=CC=C1 CKRHKYHOTKICCR-UHFFFAOYSA-K 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000007036 catalytic synthesis reaction Methods 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- PQXKDMSYBGKCJA-CVTJIBDQSA-N lurasidone Chemical compound C1=CC=C2C(N3CCN(CC3)C[C@@H]3CCCC[C@H]3CN3C(=O)[C@@H]4[C@H]5CC[C@H](C5)[C@@H]4C3=O)=NSC2=C1 PQXKDMSYBGKCJA-CVTJIBDQSA-N 0.000 description 1
- 229960001432 lurasidone Drugs 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 239000010815 organic waste Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011949 solid catalyst Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/18—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms
- B01J31/1805—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes containing nitrogen, phosphorus, arsenic or antimony as complexing atoms, e.g. in pyridine ligands, or in resonance therewith, e.g. in isocyanide ligands C=N-R or as complexed central atoms the ligands containing nitrogen
- B01J31/181—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine
- B01J31/1815—Cyclic ligands, including e.g. non-condensed polycyclic ligands, comprising at least one complexing nitrogen atom as ring member, e.g. pyridine with more than one complexing nitrogen atom, e.g. bipyridyl, 2-aminopyridine
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
- B01J31/2252—Sulfonate ligands
- B01J31/2256—Sulfonate ligands being perfluorinated, i.e. comprising at least one perfluorinated moiety as substructure in case of polyfunctional ligands
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic System without C-Metal linkages
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/30—Addition reactions at carbon centres, i.e. to either C-C or C-X multiple bonds
- B01J2231/32—Addition reactions to C=C or C-C triple bonds
- B01J2231/324—Cyclisations via conversion of C-C multiple to single or less multiple bonds, e.g. cycloadditions
- B01J2231/326—Diels-Alder or other [4+2] cycloadditions, e.g. hetero-analogues
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/02—Compositional aspects of complexes used, e.g. polynuclearity
- B01J2531/0261—Complexes comprising ligands with non-tetrahedral chirality
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/10—Complexes comprising metals of Group I (IA or IB) as the central metal
- B01J2531/16—Copper
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a preparation method of exo-Nadic anhydride, which comprises the following steps: (1) adding a solvent, maleic anhydride and a chiral catalyst D into a reaction container, and replacing air in the reaction container with nitrogen; (2) dripping cyclopentadiene at the temperature of-5 ℃, and reacting at a certain temperature after dripping; (3) after the reaction is finished, adding water for quenching, separating liquid, concentrating, crystallizing in ethanol, and filtering to obtain the exo-Nadic anhydride. The preparation method has the characteristics of high reaction stereoselectivity, high yield, good product quality, simple and convenient process operation, high stability and safety, and is suitable for industrial mass production.
Description
Technical Field
The invention relates to a method for synthesizing organic compound exterior nadic anhydride, belonging to the field of organic chemical synthesis.
Background
Nadic anhydride, also known as cis-5-norbornene-2, 3-dianhydride, has two steric isomers, endo (endo) and exo (exo) (formula I). Compared with the internal nadic anhydride, the external nadic anhydride has wider application in the synthesis research fields of resin, pesticide, medicine and the like. For example, exo-nadic anhydride is a key intermediate in the synthesis of tandospirone.
Tandospirone (Tandospirone) is an azaspirone-type anxiolytic developed by sumitomo pharmaceutical corporation of japan, Tandospirone citrate was approved in japan in 1996 and approved into china in 2003. The chemical name of the compound is (3a alpha, 4 beta, 7a alpha) -hexahydro-2- [4(4- (2-pyrimidinyl) -1-piperazinyl) butyl ] -4, 7-methylene-1H-isoindole-1, 3 (2H) -diketone dihydrocitrate, and the chemical structural formula is shown as follows:
various methods for synthesizing tandospirone have been reported, and the document [ Chem Pharm Bull,1991,39,9, 2288-. The route is as follows:
in the above synthetic route, exo-nadic anhydride is the key side chain for the synthesis of tandospirone. Regarding the synthesis of exo-type nadic anhydride, cyclopentadiene and maleic anhydride are used as starting materials, the kinetic stable product endo-configuration nadic anhydride is obtained through Diels-Alder reaction, then the endo-configuration product is transformed at high temperature to obtain crude exo-configuration nadic anhydride, and then the exo-configuration product is obtained through repeated crystallization by using a solvent. In the high-temperature transformation isomerization process, the system is easy to become viscous and easy to carbonize, the yield is low, a large amount of solvent is used in repeated recrystallization, the amount of generated organic waste liquid is large, the environment is polluted, and the three-waste treatment cost is increased.
Chinese patent CN101880274A discloses a method for converting endo-configuration nadic anhydride into exo-configuration nadic anhydride by using sodium light illumination instead of high temperature, but the method has special requirements for reaction equipment, cannot ensure the stability and strength of sodium light source in industrial production, and is difficult to realize mass production. Patent CN103848801A discloses a synthesis method for synthesizing exo-configuration nadic anhydride by one step at high temperature using dicyclopentadiene and maleic anhydride as raw materials. The method omits the cracking of dicyclopentadiene, directly uses dicyclopentadiene and improves the reaction efficiency. However, the purity of the product obtained by the method is only about 70 percent, the reaction system is still viscous and is difficult to stir, easy to carbonize and difficult to separate after-treatment, and a large amount of endo configuration products exist in the product. In order to solve the problem of low purity of exo products prepared from dicyclopentadiene, many documents report a new post-treatment purification method, and the document [ Polymer.chem., 2017,8,4707-4715 ] reports that the crude product obtained by reacting dicyclopentadiene with maleic anhydride is subjected to chlorobenzene for multiple recrystallization to obtain pure exo-configuration nadic anhydride, but the yield is only 20%.
The strategy used in the method for synthesizing exo type nadic anhydride isomerizes endo configuration, and has the problems of low yield, high energy consumption, large resource waste, environmental pollution and the like. Therefore, the research on the selective synthesis of exo configuration products by Diels-Alder reaction has great significance.
Diene and dienophile usually take endo configuration products as main parts in the Diels-Alder reaction for constructing a six-membered ring, and along with the development of asymmetric synthesis, a plurality of Lewis acids as chiral catalysts show good stereoselectivity in the Diels-Alder reaction. Lewis acid catalysts have been reported to include halides of al (iii), b (iii), fe (ii), zn (ii), ti (iv), or complex lewis acids formed from chiral diols, binaphthol, sulfonamides, and the like with metals.
The literature [ journal of extensive medical college, 1996,9, 151-. However, zinc chloride in the reaction is easy to absorb water and lose efficacy, the post-treatment is complex, and column chromatography is needed. The document [ J.Am.chem.Soc.1994,116,12115-12116] reports a sterically bulky Lewis acid ATPH prepared from aluminum and 2, 6-diphenylphenol, which catalyst selectively reacts cyclopentadiene and an α, β -unsaturated carbonyl substrate to form an exo configuration product with a maximum ratio exo: endo of 97: 3. However, the use of this catalyst has stability problems in the post-treatment, and aluminum is sensitive to pH in the post-treatment, and is liable to cause stickiness, by-products, and the like. The document Angew. chem. int. Ed.1994,33, 1856-1858 describes a chiral iron catalyst which is used to catalyze the cycloaddition reaction of a 2-substituted unsaturated aldehyde and cyclopentadiene to give a main product of exo configuration, exo: endo >95: 5. The catalyst has strict requirements on dienophile substrates, and maleic anhydride is not suitable for a reaction system.
Diels-Alder, but few reports on chiral catalytic synthesis of exo-nadic anhydride, are reported [ chem. Commun.,1996,2315-2316] which reports preparation of exo-nadic anhydride at room temperature from maleic anhydride and cyclopentadiene with exo: endo as high as 91:9 and 91% yield in water as solvent and indium trichloride as catalyst. However, the post-treatment is difficult, the viscosity is easy to change, and column chromatography is required, so that the method is not suitable for amplification.
Disclosure of Invention
The invention aims to provide a simple, efficient and safe synthesis method of exo-Nadic anhydride by Diels-Alder reaction catalyzed by a chiral catalyst aiming at the existing defects.
The invention provides a preparation method of exo-Nadic anhydride, which has the following chemical reaction formula:
in order to achieve the purpose of the invention, the invention researches a plurality of chiral catalysts to catalyze Diels-Alder reaction of maleic anhydride and cyclopentadiene to prepare exo-nadic anhydride. Through research, the invention unexpectedly discovers that the chiral Lewis acid catalyst D can catalyze the Diels-Alder reaction of maleic anhydride and cyclopentadiene to obtain exo-nadic anhydride with high stereoselectivity. The structure of chiral lewis acid catalyst D is shown below:
in order to realize the purpose of the invention, the chiral Lewis acid catalyst D of the invention catalyzes Diels-Alder reaction of maleic anhydride and cyclopentadiene, and a great deal of process parameter research is carried out.
In order to realize the purpose of the invention, the technical scheme of the invention comprises the following steps: (1) adding a solvent, maleic anhydride and a chiral catalyst D into a reaction container, and replacing air in the reaction container with nitrogen; (2) dripping cyclopentadiene at the temperature of-5 ℃, and reacting at a certain temperature after dripping; (3) after the reaction is finished, adding water for quenching, separating liquid, concentrating, crystallizing in ethanol, and filtering to obtain the exo-Nadic anhydride.
According to the scheme, the selected reaction solvent is one of dichloromethane, toluene, ethyl acetate, 2-methyltetrahydrofuran and methyl tert-butyl ether, preferably dichloromethane, and the volume dosage of the solvent is 5 times of the mass of maleic anhydride.
According to the scheme, the molar ratio of the maleic anhydride to the cyclopentadiene is 1: 1-1: 5, and preferably 1: 1.3.
According to the scheme, the selected reaction temperature is-25-15 ℃, and preferably-5 ℃.
According to the scheme, the molar quantity of the catalyst is 5-15% of that of maleic anhydride, and preferably 10%.
According to the scheme, the volume of the crystallization solvent ethanol is 5 times of the mass of the maleic anhydride.
According to the scheme, the crystallization temperature is-5-0 ℃, and the crystallization time is 4-5 hours.
The invention adopts gas chromatography to detect the product purity of the exterior Nadic anhydride, and adopts hydrogen spectrum nuclear magnetic resonance specific chemical shift integral value to calculate the proportion of endo and exo configurations.
The chiral catalyst is compound D (ref: organic chemistry, 1997,17,359-361 and J.org.chem.1998,63,4541-4544), and the synthetic route is shown below:
the beneficial technical effects of the invention are as follows: the method can synthesize the exo-Nadic anhydride with high efficiency, high selectivity and high yield. Compared with the prior art, the method saves a high-temperature transformation step, and has the characteristics of energy consumption saving, environmental protection, safety, simplicity and convenience. The purity of the obtained product is improved to 98.5 percent, the yield can reach 93 percent at most, the exo to endo ratio is 97:3 at most, the utilization rate of raw materials is greatly improved, and the production cost is reduced.
In a word, the synthetic preparation method of the exo-nadic anhydride provided by the invention has the characteristics of high reaction stereoselectivity, high yield, good product quality, simple and convenient process operation, high stability and safety, and is suitable for industrial mass production.
The invention also aims to provide the application of the synthesis method of the exo-Nadic anhydride in preparing tandospirone or lurasidone.
Detailed Description
The following exemplary embodiments are provided to illustrate the present invention, and simple replacement or improvement of the present invention by those skilled in the art is within the technical scheme of the present invention.
Example 1 preparation of chiral catalyst D
L- (-) -phenylalaninol (46.0g,304.5mmol) was added to a solution of triethylamine (30.8g,304.5mmol) in dichloromethane (150mL), and a solution of diethylmalonyl chloride (30g,152.2mmol) in dichloromethane was added dropwise under an ice-water bath and stirred at room temperature for 20 h. Adding water, stirring, standing, and separating. The organic phase was dried, concentrated, and thionyl chloride (90mL) was added to the mixture to conduct a reflux reaction at 100 ℃ for 4 hours. Vacuum concentrating to remove thionyl chloride, and crystallizing the mixed solvent of trichloromethane and normal hexane to obtain a solid. Then, the solid was dissolved in methanol (150mL), an aqueous solution of sodium hydroxide (containing 6.0g of sodium hydroxide and 90mL of water) was added dropwise, the mixture was refluxed at 85 ℃ for 2 hours, the methanol was distilled off under reduced pressure, water and chloroform were added, and the mixture was stirred, allowed to stand, and separated. The organic phase was dried over magnesium sulfate, filtered, concentrated, and purified by column chromatography to give 19.5g of a single-sided ring-closed organic ligand.
The ligand obtained above was added to an anhydrous, oxygen-free dry flask, copper (II) trifluoromethanesulfonate (16.5g,45.7mmol) and dichloromethane (100mL) were added and stirred vigorously at room temperature for 4 h. Celite was filtered through a pad, and the filtrate was collected and concentrated to give 34.7g of a pale green solid catalyst D.
EXAMPLE 2 preparation of exo-Nadic anhydride
A250 mL three-necked flask was charged with maleic anhydride (25.0g,255mmol) and methylene chloride (125 mL). Dissolve with stirring and add the home-made chiral catalyst D (19.4g,25.5 mmol). Introducing nitrogen to replace system air for three times, subsequently cooling to-5 ℃ under the protection of nitrogen, and then dropwise adding the freshly depolymerized cold cyclopentadiene monomer (33.7g,510 mol). And reacting the system for two hours at 5-15 ℃ after the dropwise addition, dropwise adding 50mL of water, raising the temperature to room temperature, stirring, separating liquid, washing the organic phase once with water, drying with sodium sulfate, and concentrating to obtain an oily substance. Adding absolute ethyl alcohol (125mL) into the oily substance, placing the oily substance at a temperature of between 5 ℃ below zero and 0 ℃, stirring and crystallizing for 4 to 5 hours, carrying out suction filtration, collecting a filter cake, and drying to obtain a product, namely the external Nadic anhydride, 37.7g, the yield of 90 percent, the purity of 93.8 percent (GC), and the exo: endo is 95.5: 4.5.
EXAMPLE 3 preparation of Exo-Nadic anhydride
A250 mL three-necked flask was charged with maleic anhydride (25.0g,255mmol) and methylene chloride (125 mL). Dissolve with stirring and add the home-made chiral catalyst D (19.4g,25.5 mmol). Introducing nitrogen to replace system air for three times, subsequently cooling to-5 ℃ under the protection of nitrogen, and then dropwise adding the freshly depolymerized cold cyclopentadiene monomer (21.9g,331.4 mol). And reacting the system for two hours at the temperature of-5 ℃ after the dropwise addition, dropwise adding 50mL of water, raising the temperature to room temperature, stirring, separating liquid, washing the organic phase once with water, drying with sodium sulfate, and concentrating to obtain an oily substance. Adding absolute ethyl alcohol (125mL) into the oily substance, placing the oily substance at a temperature of between 5 ℃ below zero and 0 ℃, stirring and crystallizing for 4 to 5 hours, carrying out suction filtration, collecting a filter cake, and drying to obtain a product of external Nadic anhydride 38.9g, wherein the yield is 93 percent, the purity is 98.5 percent (GC), and the exo: endo is 97: 3.
EXAMPLE 4 preparation of exo-Nadic anhydride
A250 mL three-necked flask was charged with maleic anhydride (25.0g,255mmol) and methylene chloride (125 mL). Dissolve with stirring and add the home-made chiral catalyst D (9.7g,12.75 mmol). Introducing nitrogen to replace system air for three times, subsequently cooling to-5 ℃ under the protection of nitrogen, and then dropwise adding the freshly depolymerized cold cyclopentadiene monomer (21.9g,331.4 mol). And reacting the system for two hours at the temperature of-5 ℃ after the dropwise addition, dropwise adding 50mL of water, raising the temperature to room temperature, stirring, separating liquid, washing the organic phase once with water, drying with sodium sulfate, and concentrating to obtain an oily substance. Adding absolute ethyl alcohol (125mL) into the oily substance, placing the oily substance at a temperature of between 5 ℃ below zero and 0 ℃, stirring and crystallizing for 4 to 5 hours, carrying out suction filtration, collecting a filter cake, and drying to obtain a product of the external nadic anhydride with the yield of 36.5g, the purity of 97.7 percent (GC) and the exo: endo ratio of 88.2: 11.8.
EXAMPLE 5 preparation of Exo-Nadic anhydride
A250 mL three-necked flask was charged with maleic anhydride (25.0g,255mmol) and methylene chloride (125 mL). Dissolve with stirring and add the home-made chiral catalyst D (29.1g,38.24 mmol). Introducing nitrogen to replace system air for three times, subsequently cooling to-5 ℃ under the protection of nitrogen, and then dropwise adding the freshly depolymerized cold cyclopentadiene monomer (21.9g,331.4 mol). And reacting the system for two hours at the temperature of-5 ℃ after the dropwise addition, dropwise adding 50mL of water, raising the temperature to room temperature, stirring, separating liquid, washing the organic phase once with water, drying with sodium sulfate, and concentrating to obtain an oily substance. Adding absolute ethyl alcohol (125mL) into the oily substance, placing the oily substance at a temperature of between 5 ℃ below zero and 0 ℃, stirring and crystallizing for 4 to 5 hours, carrying out suction filtration, collecting a filter cake, and drying to obtain a product of the external Nadic anhydride, wherein the yield is 38.2g, the purity is 97.8 percent (GC), and the exo: endo is 96.7: 3.3.
EXAMPLE 6 preparation of exo-Nadic anhydride
A250 mL three-necked flask was charged with maleic anhydride (25.0g,255mmol) and toluene (125 mL). Dissolve with stirring and add the home-made chiral catalyst D (19.4g,25.5 mmol). Introducing nitrogen to replace system air for three times, subsequently cooling to-5 ℃ under the protection of nitrogen, and then dropwise adding the freshly depolymerized cold cyclopentadiene monomer (21.9g,331.4 mol). And reacting the system for two hours at the temperature of-5 ℃ after the dropwise addition, dropwise adding 50mL of water, raising the temperature to room temperature, stirring, separating liquid, washing the organic phase once with water, drying with sodium sulfate, and concentrating to obtain an oily substance. Adding absolute ethyl alcohol (125mL) into the oily substance, placing the oily substance at a temperature of between 5 ℃ below zero and 0 ℃, stirring and crystallizing for 4 to 5 hours, carrying out suction filtration, collecting a filter cake, and drying to obtain a product of the external Nadic anhydride, wherein the yield is 35.5g, the purity is 93.3 percent (GC), and the exo: endo is 94.6: 5.4.
EXAMPLE 7 preparation of exo-Nadic anhydride
A250 mL three-necked flask was charged with maleic anhydride (25.0g,255mmol) and ethyl acetate (125 mL). Dissolve with stirring and add the home-made chiral catalyst (19.4g,25.5 mmol). Introducing nitrogen to replace system air for three times, subsequently cooling to-5 ℃ under the protection of nitrogen, and then dropwise adding the freshly depolymerized cold cyclopentadiene monomer (16.9g,255 mol). And reacting the system for two hours at the temperature of-5 ℃ after the dropwise addition, dropwise adding 50mL of water, raising the temperature to room temperature, stirring, separating liquid, washing the organic phase once with water, drying with sodium sulfate, and concentrating to obtain an oily substance. Adding absolute ethyl alcohol (125mL) into the oily substance, placing the oily substance at a temperature of between 5 ℃ below zero and 0 ℃, stirring and crystallizing for 4 to 5 hours, carrying out suction filtration, collecting a filter cake, and drying to obtain a product, namely the external Nadic anhydride, wherein the yield is 80.8%, the purity is 91.1% (GC), and the exo: endo is 90.9: 9.1.
Claims (6)
1. A preparation method of exo-nadic anhydride comprises the following steps: (1) adding a solvent, maleic anhydride and a chiral catalyst D into a reaction container, and replacing air in the reaction container with nitrogen; (2) dripping cyclopentadiene at the temperature of-5 ℃, and reacting at a certain temperature after dripping; (3) after the reaction is finished, adding water for quenching, separating liquid, concentrating, crystallizing in ethanol, and filtering to obtain the exo-Nadic anhydride.
2. The process for the preparation of exo-nadic anhydride as claimed in claim 1, wherein the reaction solvent used in step (1) is one of dichloromethane, toluene, ethyl acetate, 2-methyltetrahydrofuran, methyl t-butyl ether, and the volume of the solvent is 5 times of the mass of maleic anhydride.
3. The method for preparing exo-nadic anhydride as claimed in claim 1, wherein the chiral catalyst D used in step (1) is 5-15% by mole of maleic anhydride, and the chiral catalyst D has the following formula:
4. the method for preparing exo-nadic anhydride according to claim 1, wherein the molar ratio of maleic anhydride to cyclopentadiene in steps (1) and (2) is 1:1 to 1:5, preferably 1: 1.3.
5. The method for preparing exo-nadic anhydride according to claim 1, wherein the reaction temperature in the step (2) is-25 to 15 ℃, preferably-5 to 5 ℃.
6. The method for preparing exo-nadic anhydride according to claim 1, wherein the volume of ethanol used as the crystallization solvent in step (3) is 5 times of the mass of maleic anhydride, the crystallization temperature is-5 to 0 ℃, and the crystallization time is 4 to 5 hours.
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| CN102992992A (en) * | 2012-10-31 | 2013-03-27 | 中国石油化工股份有限公司 | Method for preparing bicyclo[2.2.1]-hept-5-ene-2,3-dicarboxylic acid disodium |
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