CN113501797B - Preparation method of exo-nadic anhydride - Google Patents
Preparation method of exo-nadic anhydride Download PDFInfo
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- CN113501797B CN113501797B CN202110934986.XA CN202110934986A CN113501797B CN 113501797 B CN113501797 B CN 113501797B CN 202110934986 A CN202110934986 A CN 202110934986A CN 113501797 B CN113501797 B CN 113501797B
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- exo
- nadic anhydride
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- cyclopentadiene
- anhydride
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- 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 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 claims abstract description 44
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 30
- 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 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- 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 16
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 239000007788 liquid Substances 0.000 claims abstract description 4
- 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 14
- 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
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 238000011112 process operation Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 22
- 238000003756 stirring Methods 0.000 description 15
- 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 description 12
- 239000000126 substance Substances 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- 238000005698 Diels-Alder reaction Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 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 8
- 229950000505 tandospirone Drugs 0.000 description 8
- 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
- 239000000178 monomer Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 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
- 238000000967 suction filtration Methods 0.000 description 5
- 230000002194 synthesizing effect Effects 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000011968 lewis acid catalyst Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- 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
- 238000004090 dissolution Methods 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- -1 4- (2-pyrimidinyl) -1-piperazinyl Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 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
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 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
- 238000006555 catalytic reaction Methods 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
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- PSCMQHVBLHHWTO-UHFFFAOYSA-K indium(iii) chloride Chemical compound Cl[In](Cl)Cl PSCMQHVBLHHWTO-UHFFFAOYSA-K 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007858 starting material 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
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- MRBFGEHILMYPTF-UHFFFAOYSA-N 1-(2-Pyrimidyl)piperazine Chemical compound C1CNCCN1C1=NC=CC=N1 MRBFGEHILMYPTF-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
- QVAZCOROEAVHOE-UHFFFAOYSA-N 2-methylidene-1-phenylbutane-1,3-dione Chemical compound CC(=O)C(=C)C(=O)C1=CC=CC=C1 QVAZCOROEAVHOE-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 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
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001299 aldehydes Chemical class 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
- 229910021529 ammonia Inorganic materials 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
- 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
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000010276 construction 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
- 238000004817 gas chromatography Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 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
- 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
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 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
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation 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
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 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 solvent, maleic anhydride and chiral catalyst D into a reaction container, and replacing air in the reaction container with nitrogen; (2) Cyclopentadiene is dripped at the temperature of-5 ℃ to 5 ℃ below zero, and the reaction is carried out at a certain temperature after the dripping is finished; (3) And adding water for quenching after the reaction is finished, 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 and high stability and safety, and is suitable for industrial mass production.
Description
Technical Field
The invention relates to a method for synthesizing exo-nadic anhydride of an organic compound, belonging to the field of organic chemical synthesis.
Background
Nadic anhydride, also known as cis-5-norbornene-2, 3-dicarboxylic anhydride, has two stereoisomers (formula I), endo (endo) and exo (exo). Compared with internal nadic anhydride, the external nadic anhydride has wider application in the synthetic 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 anxiolytic developed by the japanese sumitomo pharmaceutical corporation, tandospirone citrate was marketed in japan in 1996 and was entered into china in 2003. The chemical name of the compound is (3aα,4β,7β,7aα) -hexahydro-2- [4 (4- (2-pyrimidinyl) -1-piperazinyl) butyl ] -4, 7-methylene-1 hydrogen-isoindole-1, 3 (2 hydrogen) -diketone dihydro citrate, and the chemical structural formula is shown as follows:
there are many reported methods for synthesizing tandospirone, and literature [ Chem Pharm Bull,1991,39,9,2288-2300] reports that exo-configuration nadic anhydride is used as a starting material, cis-5-exo-2, 3-dicarboximide is obtained by Pd/C hydrogenation reduction and ammonia ammoniation at 190 ℃, and then the cis-5-exo-2, 3-dicarboximide is condensed with 1, 4-dibromobutane, and then the condensation reaction is carried out with pyrimidinyl piperazine, so as to obtain the tandospirone. The route is as follows:
in the above synthetic route, exo-nadic anhydride is a key side chain for synthesizing tandospirone. In the synthesis of exo-nadic anhydride, cyclopentadiene and maleic anhydride are generally used as starting materials, a kinetic stable product endo-nadic anhydride is obtained through Diels-Alder reaction, the endo-nadic anhydride is transformed at high temperature to obtain a crude exo-nadic anhydride product, and then the solvent is used for repeated crystallization for many times to obtain a pure exo-nadic anhydride product. In the high-temperature transformation isomerization process, the system is easy to become sticky, easy to carbonize and low in yield, and a large amount of solvents are used for repeated recrystallization, so that 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 nadic anhydride with endo configuration into nadic anhydride with exo configuration by using sodium light illumination instead of high temperature, but the method has special requirements on reaction equipment, and stability and strength of sodium light source cannot be ensured in industrial production, so that mass production is difficult to realize. Patent CN103848801a discloses a method for synthesizing exo-configuration nadic anhydride by taking dicyclopentadiene and maleic anhydride as raw materials through one step at high temperature. The method omits 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%, the reaction system is still viscous and difficult to stir, easy to carbonize, 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, a novel post-treatment purification method is reported in a plurality of documents [ Polym.chem.,2017,8,4707-4715.] and pure exo-configuration nadic anhydride is obtained by recrystallizing a crude product obtained by reacting dicyclopentadiene with maleic anhydride for a plurality of times in a yield of only 20%.
The strategies used in the method for synthesizing exo-type nadic anhydride are all isomerization of endo configuration, and the method has the problems of low yield, high energy consumption, large resource waste, environmental pollution and the like. Therefore, the research on selective synthesis of exo configuration products by Diels-Alder reaction has greater significance.
Diels-Alder reactions of diene and dienophile in the construction of six-membered rings are generally based on products of endo configuration, and with the development of asymmetric synthesis, many Lewis acids as chiral catalysts exhibit good stereoselectivity in Diels-Alder reactions. Lewis acid catalysts that have been reported include halides of Al (III), B (III), fe (II), zn (II), ti (IV), or complex Lewis acids formed from chiral diols, binaphthols, sulfonamides, etc. with metals.
Literature [ Proc.Ind. of Yanbiao, 1996,9,151-153] reports that 2-methylene-1-phenyl-1, 3-butanedione and cyclopentadiene react at-78℃under zinc chloride catalysis to give exo-configuration products, wherein exo: endo is 94:6. However, zinc chloride is prone to water absorption failure in this reaction, post-treatment is complicated, and column chromatography is required. Document [ J.am.chem.Soc.1994,116,12115-12116] reports a highly sterically hindered Lewis acid ATPH prepared from aluminum and 2, 6-diphenylphenol, which catalyst selectively reacts cyclopentadiene with an α, β -unsaturated carbonyl substrate to give a product of exo configuration in a maximum ratio exo: endo of 97:3. However, the use of this catalyst has stability problems in the post-treatment, and aluminum is more sensitive to pH in the post-treatment, and is liable to occur as a sticky, by-product, or the like. Document [ Angew.chem.int.ed.1994,33,1856-1858] describes a chiral iron catalyst with which cycloaddition of 2-substituted unsaturated aldehydes and cyclopentadiene is catalyzed to give the main product in exo configuration, exo: endo >95:5. The catalyst has strict requirements on dienophile substrates, and maleic anhydride is not suitable for the reaction system.
Many asymmetric catalytic reactions of Diels-Alder are reported, but few chiral catalytic synthesis of exo-nadic anhydride is reported, and document [ chem.commun.,1996,2315-2316] reports that exo-nadic anhydride is prepared by using maleic anhydride and cyclopentadiene at room temperature in the presence of water as a solvent and indium trichloride as a catalyst, wherein exo-nadic anhydride is prepared by using exo-nadic anhydride with a product exo of 91:9 and a yield of 91%. However, the post-treatment is difficult, the viscosity is easily changed, and column chromatography is required, which is not suitable for the amplification.
Disclosure of Invention
The invention aims to provide a simple, efficient and safe synthesis method of exterior nadic anhydride by using a Diels-Alder reaction catalyzed by a chiral catalyst aiming at the defects of the prior art.
The invention provides a preparation method of exo-nadic anhydride, which has the chemical reaction formula as follows:
in order to achieve the purpose of the invention, various chiral catalysts are studied to catalyze Diels-Alder reaction of maleic anhydride and cyclopentadiene to prepare exo-nadic anhydride. Through researches, the invention unexpectedly discovers that the chiral Lewis acid catalyst D catalyzes Diels-Alder reaction of maleic anhydride and cyclopentadiene, and can obtain exo-nadic anhydride with high stereoselectivity. The structure of chiral lewis acid catalyst D is shown below:
in order to achieve the purpose of the invention, the chiral Lewis acid catalyst D catalyzes Diels-Alder reaction of maleic anhydride and cyclopentadiene, and a great deal of technological parameter research is carried out.
In order to achieve the purpose of the invention, the technical scheme of the invention comprises the following steps: (1) Adding solvent, maleic anhydride and chiral catalyst D into a reaction container, and replacing air in the reaction container with nitrogen; (2) Cyclopentadiene is dripped at the temperature of-5 ℃ to 5 ℃ below zero, and the reaction is carried out at a certain temperature after the dripping is finished; (3) And adding water for quenching after the reaction is finished, 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 tertiary butyl ether, preferably dichloromethane, and the volume consumption of the solvent is 5 times of the mass of maleic anhydride.
According to the above scheme, the molar ratio of maleic anhydride to cyclopentadiene is 1:1-1:5, preferably 1:1.3.
According to the above scheme, the reaction temperature is selected to be-25 to 15 ℃, preferably-5 to 5 ℃.
According to the scheme, the molar quantity of the catalyst is 5-15% of the molar quantity of maleic anhydride, preferably 10%.
According to the scheme, the volume amount of ethanol serving as the crystallization solvent is 5 times of the mass of 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 exo-nadic anhydride and adopts hydrogen spectrum nuclear magnetic resonance specific chemical shift integral value to calculate the ratio of endo and exo configurations.
Chiral catalysts are compounds D (ref: organic chemistry, 1997,17,359-361 and J.org.chem.1998,63, 4541-4544) whose synthetic routes are 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 omits the high-temperature transformation step, and has the characteristics of energy consumption conservation, more environmental protection, safety and simplicity. The purity of the obtained product is improved to 98.5%, the highest yield can reach 93%, and the highest exo: endo is 97:3, so that the utilization rate of raw materials is greatly improved, and the production cost is reduced.
In a word, the synthesis and preparation method of 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.
Another object of the present invention is to provide the use of the synthesis method of exo-nadic anhydride in the preparation of tandospirone or lurasidone.
Detailed Description
The following exemplary embodiments are provided to illustrate the present invention, and simple substitutions or modifications of the present invention by those skilled in the art are within the scope of the present invention.
Example 1 preparation of chiral catalyst D
L- (-) -phenylalaninol (46.0 g,304.5 mmol) was added to a dichloromethane (150 mL) solution containing triethylamine (30.8 g,304.5 mmol), and a dichloromethane solution of diethylmalonyl chloride (30 g,152.2 mmol) was added dropwise to the solution under ice-water bath, followed by stirring at room temperature for 20 hours. Adding water, stirring, standing, and separating. The organic phase was dried, concentrated, and thionyl chloride (90 mL) was added thereto, followed by reflux reaction at 100℃for 4 hours. Concentrating under reduced pressure to remove thionyl chloride, crystallizing the mixed solvent of chloroform and normal hexane to obtain a solid. Then, the solid was dissolved in methanol (150 mL), an aqueous sodium hydroxide solution (containing 6.0g of sodium hydroxide, 90mL of water) was added dropwise, the mixture was refluxed at 85℃for 2 hours, 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 the organic ligand having one-sided ring closure.
The ligand obtained above was charged into a flask dried anhydrous and oxygen-free, copper (II) triflate (16.5 g,45.7 mmol) and methylene chloride (100 mL) were added and stirred vigorously at room temperature for 4h. The filtrate was collected by filtration through celite and concentrated to give 34.7g of catalyst D as a pale green solid.
EXAMPLE 2 preparation of exo-nadic anhydride
To a 250mL three-necked flask, maleic anhydride (25.0 g,255 mmol) and methylene chloride (125 mL) were added. Stirring and dissolving, add homemade chiral catalyst D (19.4 g,25.5 mmol). The system air was replaced three times with nitrogen, then cooled to-5 ℃ under nitrogen protection, and then freshly depolymerized cold cyclopentadiene monomer (33.7 g,510 mol) was added dropwise. After the dripping is finished, the system reacts for two hours at the temperature of 5-15 ℃, 50mL of water is dripped, the temperature is raised to the room temperature, the mixture is stirred and separated, and the organic phase is washed once again with water, dried with sodium sulfate and concentrated to obtain oily matter. Absolute ethyl alcohol (125 mL) is added into the oily substance, the oily substance is placed at the temperature of between minus 5 and 0 ℃ for stirring and crystallization for 4 to 5 hours, the filtration is carried out, filter cakes are collected, the product is dried, 37.7g of exo-nadic anhydride is obtained, the yield is 90 percent, the purity is 93.8 percent (GC), and exo: endo is 95.5:4.5.
EXAMPLE 3 preparation of exo-nadic anhydride
To a 250mL three-necked flask, maleic anhydride (25.0 g,255 mmol) and methylene chloride (125 mL) were added. Stirring and dissolving, add homemade chiral catalyst D (19.4 g,25.5 mmol). The system air was replaced three times with nitrogen, and then cooled to-5 to 5℃under nitrogen protection, and then freshly depolymerized cold cyclopentadiene monomer (21.9 g,331.4 mol) was added dropwise. After the dripping is finished, the system reacts for two hours at the temperature of between 5 ℃ below zero and 5 ℃, 50mL of water is dripped, the temperature is raised to the room temperature, the mixture is stirred and separated, the organic phase is washed once again with water, dried with sodium sulfate and concentrated to obtain oily matter. Absolute ethyl alcohol (125 mL) is added into the oily substance, the oily substance is placed at the temperature of between minus 5 and 0 ℃ for stirring and crystallization for 4 to 5 hours, suction filtration is carried out, filter cakes are collected, and the product is dried, thus 38.9g of exo-nadic anhydride is obtained, the yield is 93 percent, the purity is 98.5 percent (GC), and exo: endo is 97:3.
EXAMPLE 4 preparation of exo-nadic anhydride
To a 250mL three-necked flask, maleic anhydride (25.0 g,255 mmol) and methylene chloride (125 mL) were added. Stirring for dissolution, self-made chiral catalyst D (9.7 g,12.75 mmol) was added. The system air was replaced three times with nitrogen, and then cooled to-5 to 5℃under nitrogen protection, and then freshly depolymerized cold cyclopentadiene monomer (21.9 g,331.4 mol) was added dropwise. After the dripping is finished, the system reacts for two hours at the temperature of between 5 ℃ below zero and 5 ℃, 50mL of water is dripped, the temperature is raised to the room temperature, the mixture is stirred and separated, the organic phase is washed once again with water, dried with sodium sulfate and concentrated to obtain oily matter. Absolute ethyl alcohol (125 mL) is added into the oily substance, the oily substance is placed at the temperature of between minus 5 and 0 ℃ for stirring and crystallization for 4 to 5 hours, suction filtration is carried out, filter cakes are collected, and the product is dried, thus 36.5g of exo-nadic anhydride with the yield of 87 percent and the purity of 97.7 percent (GC) is obtained, and exo: endo is 88.2:11.8.
EXAMPLE 5 preparation of exo-nadic anhydride
To a 250mL three-necked flask, maleic anhydride (25.0 g,255 mmol) and methylene chloride (125 mL) were added. Stirring for dissolution, homemade chiral catalyst D (29.1 g,38.24 mmol) was added. The system air was replaced three times with nitrogen, and then cooled to-5 to 5℃under nitrogen protection, and then freshly depolymerized cold cyclopentadiene monomer (21.9 g,331.4 mol) was added dropwise. After the dripping is finished, the system reacts for two hours at the temperature of between 5 ℃ below zero and 5 ℃, 50mL of water is dripped, the temperature is raised to the room temperature, the mixture is stirred and separated, the organic phase is washed once again with water, dried with sodium sulfate and concentrated to obtain oily matter. Absolute ethyl alcohol (125 mL) is added into the oily matter, the oily matter is placed at the temperature of between minus 5 and 0 ℃ for stirring and crystallization for 4 to 5 hours, suction filtration is carried out, filter cakes are collected, and the product is dried, thus 38.2g of exo-nadic anhydride is obtained, the yield is 91.3 percent, the purity is 97.8 percent (GC), and exo is 96.7:3.3.
EXAMPLE 6 preparation of exo-nadic anhydride
To a 250mL three-necked flask, maleic anhydride (25.0 g,255 mmol) and toluene (125 mL) were added. Stirring and dissolving, add homemade chiral catalyst D (19.4 g,25.5 mmol). The system air was replaced three times with nitrogen, and then cooled to-5 to 5℃under nitrogen protection, and then freshly depolymerized cold cyclopentadiene monomer (21.9 g,331.4 mol) was added dropwise. After the dripping is finished, the system reacts for two hours at the temperature of between 5 ℃ below zero and 5 ℃, 50mL of water is dripped, the temperature is raised to the room temperature, the mixture is stirred and separated, the organic phase is washed once again with water, dried with sodium sulfate and concentrated to obtain oily matter. Absolute ethyl alcohol (125 mL) is added into the oily substance, the oily substance is placed at the temperature of between minus 5 and 0 ℃ for stirring and crystallization for 4 to 5 hours, suction filtration is carried out, filter cakes are collected, and the filter cakes are dried, thus obtaining 35.5g of the product appearance nadic anhydride with the yield of 84.8 percent and the purity of 93.3 percent (GC), and exo: endo is 94.6:5.4.
EXAMPLE 7 preparation of exo-nadic anhydride
To a 250mL three-necked flask, maleic anhydride (25.0 g,255 mmol) and ethyl acetate (125 mL) were added. Stirring for dissolution, and adding homemade chiral catalyst (19.4 g,25.5 mmol). The system air was replaced three times with nitrogen, and then cooled to-5 ℃ under nitrogen protection, and then freshly depolymerized cold cyclopentadiene monomer (16.9 g,255 mol) was added dropwise. After the dripping is finished, the system reacts for two hours at the temperature of between 5 ℃ below zero and 5 ℃, 50mL of water is dripped, the temperature is raised to the room temperature, the mixture is stirred and separated, the organic phase is washed once again with water, dried with sodium sulfate and concentrated to obtain oily matter. Absolute ethyl alcohol (125 mL) is added into the oily matter, the oily matter is placed at the temperature of between minus 5 and 0 ℃ for stirring and crystallization for 4 to 5 hours, suction filtration is carried out, filter cakes are collected, and the filter cakes are dried, thus obtaining 33.8g of the product appearance nadic anhydride, the yield is 80.8 percent, the purity is 91.1 percent (GC), and exo: endo is 90.9:9.1.
Claims (5)
1. A preparation method of exo-nadic anhydride comprises the following steps: (1) Adding solvent, maleic anhydride and chiral catalyst D into a reaction container, and replacing air in the reaction container with nitrogen; the chiral catalyst D has the following structural formula:
；
(2) Cyclopentadiene is dropwise added at the temperature of-5 to 5 ℃, and after the cyclopentadiene is dropwise added, the cyclopentadiene is reacted at the temperature of-25 to 15 ℃; (3) Adding water for quenching after the reaction is finished, separating liquid, concentrating, crystallizing in ethanol, and filtering to obtain the exo-nadic anhydride;
wherein the reaction solvent used in the step (1) is one of dichloromethane, toluene, ethyl acetate, 2-methyltetrahydrofuran and methyl tertiary butyl ether.
2. The process for preparing exo-nadic anhydride according to claim 1, wherein the volume amount of the solvent is 5 times the mass of maleic anhydride.
3. The process for preparing exo-nadic anhydride according to claim 1, wherein the chiral catalyst D is used in the step (1) in an amount of 5 to 15% by mole of maleic anhydride.
4. The method for preparing exo-nadic anhydride according to claim 1, wherein the molar ratio of maleic anhydride to cyclopentadiene used in the step (1) and the step (2) is 1:1 to 1:5.
5. The process for preparing exo-nadic anhydride according to claim 1 or 4, wherein the molar ratio of maleic anhydride to cyclopentadiene used in the step (1) and the step (2) is 1:1.3.
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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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