CN104163759A - New synthesis methods of caronic acid and caronic anhydride - Google Patents
New synthesis methods of caronic acid and caronic anhydride Download PDFInfo
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- CN104163759A CN104163759A CN201410364816.2A CN201410364816A CN104163759A CN 104163759 A CN104163759 A CN 104163759A CN 201410364816 A CN201410364816 A CN 201410364816A CN 104163759 A CN104163759 A CN 104163759A
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- QKAHKEDLPBJLFD-UHFFFAOYSA-N 6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2,4-dione Chemical compound O=C1OC(=O)C2C1C2(C)C QKAHKEDLPBJLFD-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000001308 synthesis method Methods 0.000 title abstract 4
- MSPJNHHBNOLHOC-UHFFFAOYSA-N 3,3-dimethylcyclopropane-1,2-dicarboxylic acid Chemical compound CC1(C)C(C(O)=O)C1C(O)=O MSPJNHHBNOLHOC-UHFFFAOYSA-N 0.000 title abstract 3
- -1 caronaldehydic acid hemiacetal Chemical class 0.000 claims abstract description 21
- 239000002253 acid Substances 0.000 claims description 49
- 238000006243 chemical reaction Methods 0.000 claims description 39
- 239000007864 aqueous solution Substances 0.000 claims description 30
- 239000002994 raw material Substances 0.000 claims description 30
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- 230000001590 oxidative effect Effects 0.000 claims description 16
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 16
- 238000010189 synthetic method Methods 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 150000001875 compounds Chemical class 0.000 claims description 12
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 9
- 230000001105 regulatory effect Effects 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- 230000000903 blocking effect Effects 0.000 claims description 8
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 150000001879 copper Chemical class 0.000 claims description 6
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 238000007363 ring formation reaction Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000007259 addition reaction Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- 229910052710 silicon Inorganic materials 0.000 claims description 4
- 239000010703 silicon Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- ASUAYTHWZCLXAN-UHFFFAOYSA-N prenol Chemical compound CC(C)=CCO ASUAYTHWZCLXAN-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical group C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- IAKGBVASKQFZLZ-UHFFFAOYSA-N S(=O)(=O)=[Cu].C(F)(F)F Chemical compound S(=O)(=O)=[Cu].C(F)(F)F IAKGBVASKQFZLZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 claims description 2
- 229960003280 cupric chloride Drugs 0.000 claims description 2
- 229940045803 cuprous chloride Drugs 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- AAAQKTZKLRYKHR-UHFFFAOYSA-N triphenylmethane Chemical group C1=CC=CC=C1C(C=1C=CC=CC=1)C1=CC=CC=C1 AAAQKTZKLRYKHR-UHFFFAOYSA-N 0.000 claims description 2
- 125000005011 alkyl ether group Chemical group 0.000 claims 2
- 150000008064 anhydrides Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 239000007858 starting material Substances 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 4
- 125000004494 ethyl ester group Chemical group 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 abstract description 2
- 239000002912 waste gas Substances 0.000 abstract description 2
- CPJRRXSHAYUTGL-UHFFFAOYSA-N isopentenyl alcohol Natural products CC(=C)CCO CPJRRXSHAYUTGL-UHFFFAOYSA-N 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- BWRHOYDPVJPXMF-UHFFFAOYSA-N carane Chemical compound C1C(C)CCC2C(C)(C)C12 BWRHOYDPVJPXMF-UHFFFAOYSA-N 0.000 description 28
- 230000005311 nuclear magnetism Effects 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 229930006741 carane Natural products 0.000 description 14
- 150000002596 lactones Chemical class 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 125000004802 cyanophenyl group Chemical group 0.000 description 9
- YVPJCJLMRRTDMQ-UHFFFAOYSA-N ethyl diazoacetate Chemical compound CCOC(=O)C=[N+]=[N-] YVPJCJLMRRTDMQ-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000003810 ethyl acetate extraction Methods 0.000 description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 8
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 235000010265 sodium sulphite Nutrition 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 150000005215 alkyl ethers Chemical group 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 0 CC(C)(C12)*1C(O)OC2=O Chemical compound CC(C)(C12)*1C(O)OC2=O 0.000 description 1
- HMXQJRZLALMJHY-UHFFFAOYSA-N CCOC(C1C(C)(C)C1COC(c1cc([N+]([O-])=O)ccc1)=O)=O Chemical compound CCOC(C1C(C)(C)C1COC(c1cc([N+]([O-])=O)ccc1)=O)=O HMXQJRZLALMJHY-UHFFFAOYSA-N 0.000 description 1
- 235000007516 Chrysanthemum Nutrition 0.000 description 1
- 244000189548 Chrysanthemum x morifolium Species 0.000 description 1
- 239000005892 Deltamethrin Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical group [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- LHHCSNFAOIFYRV-DOVBMPENSA-N boceprevir Chemical compound O=C([C@@H]1[C@@H]2[C@@H](C2(C)C)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)NC(C(=O)C(N)=O)CC1CCC1 LHHCSNFAOIFYRV-DOVBMPENSA-N 0.000 description 1
- 229960000517 boceprevir Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 229960002483 decamethrin Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- OWZREIFADZCYQD-NSHGMRRFSA-N deltamethrin Chemical compound CC1(C)[C@@H](C=C(Br)Br)[C@H]1C(=O)O[C@H](C#N)C1=CC=CC(OC=2C=CC=CC=2)=C1 OWZREIFADZCYQD-NSHGMRRFSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 108700039708 galantide Proteins 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 239000002917 insecticide Substances 0.000 description 1
- 229960004534 orgotein Drugs 0.000 description 1
- 108010070915 orgotein Proteins 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- TUGDLVFMIQZYPA-UHFFFAOYSA-N tetracopper;tetrazinc Chemical compound [Cu+2].[Cu+2].[Cu+2].[Cu+2].[Zn+2].[Zn+2].[Zn+2].[Zn+2] TUGDLVFMIQZYPA-UHFFFAOYSA-N 0.000 description 1
- 230000001018 virulence Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C67/347—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by addition to unsaturated carbon-to-carbon bonds
-
- 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
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
Abstract
The invention relates to new synthesis methods of caronaldehydic acid hemiacetal, caronic acid and caronic anhydride. Hydroxyl-protected isopentenyl alcohol is adopted as a starting material, then a three-membered ring key intermediate is generated through addition of a double bond, followed by, ethyl ester and a protection group are hydrolyzed, and then caronaldehydic acid hemiacetal and caronic acid are respectively obtained by controlling oxidation conditions. The synthesis methods have the advantages of mild conditions, high production safety, and easy industrialized production; no metal residue and other waste liquids, waste residues and waste gas having pollution to the environment are generated; and the synthesis methods can effectively reduce the cost.
Description
Patent application of the present invention is divisional application, and the application number of original bill is 201110247811.8, and the applying date is on August 24th, 2011, and denomination of invention is: the novel synthesis of carane aldehydic acid lactone, the acid of card dragon, Caronic anhydride and key intermediate thereof.
Technical field
The present invention relates to the novel synthesis of carane aldehydic acid lactone, the acid of card dragon, Caronic anhydride and key intermediate thereof.
Background technology
Carane aldehydic acid lactone (Caronaldehydic acid hemiacetal) is the important intermediate of producing the Deltamethrin (molecular formula is as follows) that in current chrysanthemum ester insecticide, virulence is the highest, be widely used in agricultural chemicals and field of medicaments, its molecular formula is as follows.
Blocking imperial acid is the raw material of producing the third orgotein enzyme inhibitors boceprevir important intermediate Caronic anhydride, and the while is widespread use and agricultural chemicals and other organic synthesis fields also, and their chemical formula is as follows:
The general synthetic route of carane aldehydic acid lactone is as follows at present:
This route is synthetic carane aldehydic acid lactone taking chrysanthemumic acid ethyl ester as starting material, and this raw material production producer is less, on the high side.In ensuing oxidizing reaction, use ozone as oxygenant, power consumption is large, and operational hazards easily sets off an explosion, and ozone is to environment simultaneously.
The general synthetic route of Caronic anhydride is as follows at present:
The dragon acid taking chrysanthemumic acid ethyl ester as starting material Synthesis Card equally in this route, this raw material production producer is less, on the high side.The a large amount of potassium permanganate using in ensuing oxidizing reaction is as oxygenant, and operational hazards is held fire hazardous, and a large amount of manganese residues that contain that simultaneously generate are to environment.In oxidizing reaction, the usage quantity of acetone is very large simultaneously, and after reclaiming, cannot continue to use in this reaction, and production cost is improved greatly.
Summary of the invention
The object of the invention is to overcome defect of the prior art, a kind of method of provide synthetic carane aldehydic acid lactone, blocking imperial acid and Caronic anhydride.With more economical, safer, more the method for environmental protection realizes the manufacture of this product, improves yield and quality, reduces costs, and economizes on resources and the energy.
It is starting material that the present invention adopts the protected prenol of hydroxyl, generates triatomic ring key intermediate by the addition to two keys, next to ethyl ester and protecting group hydrolysis, then obtains respectively carane aldehydic acid lactone and the acid of card dragon by controlling oxidizing condition.Finally obtain Caronic anhydride by the cyclization of card dragon acid.General reaction route is as follows:
First this provide a kind of 3-methylol-2, and the synthetic method of 2-dimethyl ethylene-acetic acid, comprises the following steps:
1) taking the protected prenol of hydroxyl (I) as raw material; Two keys of raw material are carried out to addition reaction with the compound of formula II, obtain triatomic ring intermediate (III);
2) to the reaction that is hydrolyzed of the ethoxycarbonyl on triatomic ring intermediate (III), and deprotection base R, 3-methylol-2 obtained, 2-dimethyl ethylene-acetic acid (IV);
Reaction scheme is as follows:
In formula: R is blocking group; R
1for optionally replacement or unsubstituted alkyl, optionally replacement or unsubstituted assorted alkyl, optionally replacement or unsubstituted cycloalkyl, optionally replacement or unsubstituted Heterocyclylalkyl, optionally replacement or unsubstituted aryl and optionally replacement or unsubstituted heteroaryl.
Preferably, described blocking group R is selected from ester class protecting group, alkyl ether protecting group and silicon ethers protecting group.Further, described ester class protecting group can be selected but be not limited to ethanoyl, benzoyl or substituted benzoyl (as p-nitrophenyl formyl radical, m-nitro benzoyl, to anisoyl); Described alkyl ether protecting group can be selected but be not limited to benzyl, triphenyl methane base or THP trtrahydropyranyl; Described silicon ethers protecting group can be selected but be not limited to trimethyl silicon based or the dimethyl tertiary butyl is silica-based.
Preferably, R
1for methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl or benzyl; Most preferably be ethyl.
Step 1) in, described addition reaction is taking copper class catalyzer as catalyzer, and reaction solvent is selected from one or more the mixing in ethylene dichloride, methylene dichloride or toluene, and temperature of reaction is 25～110 DEG C.
Preferably, described copper class catalyzer be selected from that metallic copper, cuprous chloride, cuprous bromide, cuprous iodide, trifluoromethanesulfonic acid are cuprous, one or more in copper sulfate, neutralized verdigris, fluoroform sulphonyl copper and cupric chloride.
Preferably, the mol ratio of raw material 1-RO base-3-methyl-3-butylene and formula II compound is (0.5～1.5): 1, and the weight ratio of copper class catalyzer and raw material 1-RO base-3-methyl-3-butylene is (0.01～0.5): 1.
Step 2) in, described hydrolysis reaction condition is the popular response condition that is hydrolyzed ethoxycarbonyl in this area, for example: described hydrolysis reaction carries out in the aqueous solution of sodium hydroxide, temperature of reaction is preferably 50 DEG C.In described aqueous sodium hydroxide solution, contain sodium hydroxide 15～30wt%.Described deprotection base R, can be according to the method for corresponding deprotection base in blocking group employing this area of specifically selecting.
Further, the synthetic method of carane aldehydic acid lactone provided by the present invention, comprises step: make 3-methylol-2,2-dimethyl ethylene-acetic acid is soluble in water, and regulating pH value is 7～11, then carries out oxidizing reaction; The condition of described oxidizing reaction is: at-5～15 DEG C, add organic solvent, Potassium Bromide and tetramethyl piperidine oxide compound, and drip the aqueous solution of clorox; Then react temperature to 20～25 DEG C that raise; Completely rear separation of oxidizing reaction obtains product carane aldehydic acid lactone.Wherein:
Tetramethyl piperidine oxide compound and 3-methylol-2, the mass ratio of 2-dimethyl ethylene-acetic acid is (0.01～0.5): 1, be preferably (0.01～0.2): 1; Weight proportion between Potassium Bromide, tetramethyl piperidine oxide compound and the aqueous solution of clorox is 1:(0.1～0.5): (50～100), are preferably 1:(0.2～0.4): (50～100); Cl content in described aqueous sodium hypochlorite solution is 5～15wt%; The envelope-bulk to weight ratio of described organic solvent and tetramethyl piperidine oxide compound is (0.5～50): 1ml/g.
Preferably, described organic solvent is selected from acetonitrile or ethyl acetate.
Described separation method can be: after reacting completely, pour reaction system into 0 DEG C of following sodium sulfite aqueous solution, with salt acid for adjusting pH to 5, re-use ethyl acetate extraction, the organic phase extracting is dry, and then removal of solvent under reduced pressure, can obtain product carane aldehydic acid lactone.
Described 3-methylol-2,2-dimethyl ethylene-acetic acid can adopt above-mentioned any one synthetic 3-methylol-2 provided by the present invention, the method preparation of 2-dimethyl ethylene-acetic acid (IV).Wherein, described step 2) in, the ethoxycarbonyl on triatomic ring intermediate (III) is hydrolyzed after reaction deprotection base, do not carry out aftertreatment, directly lowering the temperature and regulating its pH value is 7～11, then carries out follow-up oxidizing reaction.
The synthetic route of above-mentioned carane aldehydic acid lactone is as follows:
Further, the synthetic method of card dragon provided by the present invention acid, comprises step: make 3-methylol-2,2-dimethyl ethylene-acetic acid is soluble in water, and regulating pH value is 8～10, then carries out oxidizing reaction; The condition of described oxidizing reaction is: at-5～15 DEG C, add organic solvent, Potassium Bromide and tetramethyl piperidine oxide compound, and drip the aqueous solution of clorox, then stir 10～50min, regulate again pH value to 4～7, drip the aqueous solution of Textone, after dropwising, react; Completely rear separation of oxidizing reaction obtains the acid of product card dragon.Wherein:
Tetramethyl piperidine oxide compound and 3-methylol-2, the mass ratio of 2-dimethyl ethylene-acetic acid is (0.01～0.5): 1, be preferably (0.01～0.2): 1; Weight proportion between Potassium Bromide, tetramethyl piperidine oxide compound, the aqueous solution of clorox and the aqueous solution of Textone is 1:(0.1～0.5): (50～100): (30～100), are preferably 1:(0.2～0.4): (50～100): (30～100); Cl content in the aqueous solution of described aqueous sodium hypochlorite solution and Textone is respectively 5～15wt%; The envelope-bulk to weight ratio of described organic solvent and tetramethyl piperidine oxide compound is (0.5～50): 1ml/g.
Preferably, described organic solvent is selected from acetonitrile or ethyl acetate.
Described separation method can be: after reacting completely, pour reaction system into 0 DEG C of following sodium sulfite aqueous solution, with salt acid for adjusting pH to 1, re-use ethyl acetate extraction, the organic phase extracting is dry, and then removal of solvent under reduced pressure can obtain the acid of product card dragon.
Described 3-methylol-2,2-dimethyl ethylene-acetic acid can adopt above-mentioned any one synthetic 3-methylol-2 provided by the present invention, the method preparation of 2-dimethyl ethylene-acetic acid (IV).Wherein, described step 2) in, the ethoxycarbonyl on triatomic ring intermediate (III) is hydrolyzed after reaction deprotection base, do not carry out aftertreatment, directly lowering the temperature and regulating its pH value is 8～10, then carries out follow-up oxidizing reaction.
The synthetic route of above-mentioned card dragon acid is as follows:
Further, the invention also discloses a kind of synthetic method of Caronic anhydride, comprise step: make the imperial acid of card carry out ring-closure reaction and obtain product Caronic anhydride; The acid of described card dragon is prepared by the method that adopts above-mentioned any one Synthesis Card dragon acid.
Preferably, described ring-closure reaction, taking aceticanhydride as solvent, carries out under the reflux temperature of aceticanhydride, and the reaction times is 2-4h.
The synthetic route of above-mentioned Caronic anhydride is as follows:
Compared with prior art, above-mentioned carane aldehydic acid lactone provided by the present invention, the synthetic method of blocking imperial acid and Caronic anhydride, have the following advantages:
1) mild condition, production security is high, is easy to suitability for industrialized production;
2) without metallic residue and other, environment there is is the waste liquid of pollution, waste residue, waste gas generates;
3) supplementary material is all cheap and easy to get, can effectively reduce costs.
Embodiment
Further set forth the present invention below in conjunction with embodiment.Should be understood that these embodiment are only for the present invention is described, but not limit the scope of the invention.
Embodiment 1a
The preparation of intermediate III a:
In reaction flask, add intermediate compound I a (54g), (0.5g), ethylene dichloride 200ml, is warming up to 60-65 DEG C to copper catalyst (catalyzer is the cuprous complex compound with cyanophenyl 1:1 of trifluoromethanesulfonic acid).To the solution that drips 48 grams of ethyl diazoacetate II in system and be dissolved in ethylene dichloride 100ml, within keeping, under the condition of warm 60-85 DEG C, drip off.Dripping off rear continuation stirs 30 minutes.Underpressure distillation, the cut of collecting 117-120 DEG C/1kPa obtains intermediate III a 60g.
Trans IIIa nuclear-magnetism:
1HNMRδ4.18(dd,J＝12,7Hz?1H),4.13(m,2H),4.00(dd,J＝12,8Hz,1H),2.07(s,3H),1.73(ddd,J＝8,7,5.5Hz,1H),1.43(d,J＝5.5Hz,1H),1.27(s,3H),1.26(t,J＝7Hz,3H),1.19(s,3H)
Cis IIIa nuclear-magnetism:
1HNMR:δ4.50(dd,J＝12,7Hz,1H),4.39(dd,J＝12,8Hz,1H),4.11(m,2H),2.06(s,3H),1.60(d,J＝9Hz,1H),1.44(ddd,J＝9.8,7Hz,1H),1.27(s,3H),1.25(t,J＝7Hz,3H),1.19(s,3H)
Embodiment 1b
The preparation of intermediate III b:
Operation is with example Ia: wherein catalyzer complex compound with cyanophenyl 1:1 cuprous for trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material Ib is 0.01, the mol ratio of raw material Ib and ethyl diazoacetate II is 1:1.5.
Trans IIIb nuclear-magnetism:
1HNMR:δ4.12(m,2H),3.74(dd,J＝11,6Hz,1H),3.53(dd,J＝11,8Hz,1H),1.66(ddd,J＝8,6,5.5Hz,1H),1.33(d,J＝5Hz,1H),1.26(t,J＝7Hz,3H),1.23(s,3H),1.18(s,3H),0.10(s,9H)
Cis IIIb nuclear-magnetism:
1HNMR:δ4.08(m,2H),3.91(dd,J＝6.5,2.5Hz,2H),1.52(d,J＝9Hz,1H),1.40(ddd,J＝9,6.52.5Hz,1H),1.25(s,3H),1.25(t,J＝7Hz,3H),1.18(s,3H),0.10(s,9H)
Embodiment 1c
The preparation of intermediate III c:
Operation is with example Ia: wherein catalyzer is the cuprous complex compound with cyanophenyl 1:1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material Ic is 0.01, and the mol ratio of raw material Ic and ethyl diazoacetate II is 1:1.5.
Trans IIIc nuclear-magnetism:
1HNMR:δ4.12(m,2H),3.77(dd,J＝11,6Hz,1H),3.55(dd,J＝11,8Hz,1H),1.63(ddd,J＝9,6,5Hz,1H),1.35(d,J＝5Hz,1H),1.24(t,J＝7Hz,3H),1.22(s,3H),1.18(s,3H),0.89(s,9H),0.06(s,3H),0,05(s,3H)
Cis IIIc nuclear-magnetism:
1HNMR:δ4.08(m,2H),3.96(dd,J＝11,7Hz,1H),3.90(dd,J＝11,6.5Hz,1H),1.52(d,J＝9Hz,1H),1.40(ddd,J＝9,7,6.5Hz,1H),1.25(s,3H),1.25(t,J＝7Hz,3H),1.18(s,3H),0.89(s,9H),0.06(s,3H),0.05(s,3H)
Embodiment 1d
The preparation of intermediate III d:
Operation is with example Ia: wherein catalyzer is the cuprous complex compound with cyanophenyl 1:1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material Id is 0.01, and the mol ratio of raw material Id and ethyl diazoacetate II is 1:1.5.
Trans IIId nuclear-magnetism:
1HNMR:δ7.35-7.25(m,5H),4.50(d,J＝1Hz,2H),4.11(m,2H)3.61(dd,J＝11,6Hz,1H),3.38(dd,J＝11,8.5Hz,1H),1.75(ddd,J＝8.5,6,5Hz,1H),1.36(d,J＝5Hz,1H),1.25(t,J＝7Hz,3H),1.24(s,3H),1.18(s,3H)
Cis IIId nuclear-magnetism:
1HNMR:δ7.35-7.25(m,5H),4.52(d,J＝1Hz,2H),4.11(m,2H),3.86(dd,J＝10.5,5Hz,1H),3.78(dd,J＝10.5,4.5Hz,1H),1.57(d,J＝9Hz,1H),1.44(ddd,J＝9,5,5.5,1H),1.25(s,3H),1.24(t,J＝7Hz,3H),1,19(s,3H).
Embodiment 1e
The preparation of intermediate III e:
Operation is with example Ia: wherein catalyzer is the cuprous complex compound with cyanophenyl 1:1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material Ie is 0.01, and the mol ratio of raw material Ie and ethyl diazoacetate II is 1:1.5.
Trans IIIe nuclear-magnetism:
1HNMR:δ7.50-7.40(m,6H),7.35-7.15(m,9H),4,10(m,2H),3.31(dd,J＝10,6Hz,1H),2.85(dd,J＝10,8.5Hz,1H),1.75(ddd,J＝8.5,6,5Hz,1H),1.32(d,J＝5Hz,1H),1,28(t,J＝7Hz,3H),1,26(s,3H),1.02(s,3H)
Cis IIIe nuclear-magnetism:
1HNMR:δ7.50-7.40(m,6H),7.35-7.15(m,9H),3.98(m,2H),3.43(dd,J＝7,0.5Hz,2H),1.50(d,J＝9Hz,1H),1.37(dt,J＝9,7Hz,1H),1.18(s,3H),1.17(t,J＝7Hz,3H),1.09(s,3H).
Embodiment 1f
The preparation of intermediate III f:
Operation is with example Ia: wherein catalyzer is the cuprous complex compound with cyanophenyl 1:1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material If is 0.01, and the mol ratio of raw material And if ethyl diazoacetate II is 1:1.5.
Trans IIIf nuclear-magnetism:
1HNMR:δ8.10-8.00(m,2H),7.62-7.38(m,3H),4.48(dd,J＝12,7Hz,1H),4.23(dd,J＝12,9Hz,1H),4.14(m,2H),1.88(ddd,J＝9,7,5Hz,1H),1.53(d,J＝5Hz,1H),1.27(s,3H),1.26(t,J＝7Hz,3H),1.26(s,3H)
Cis IIIf nuclear-magnetism:
1HNMR:δ8.10-8.00(m,2H),7.62-7.38(m,3H),4.73(ddd,J＝22,7,1Hz,1H),4.68(ddd,J＝22,5.5,2Hz,1H),4.10(m,2H),1.75-1.52(m,2H),1.35(s,3H),1.26(t,J＝7Hz,3H),1.22(s,3H)
Embodiment 1g
The preparation of intermediate III g:
Operation is with example Ia: wherein catalyzer is the cuprous complex compound with cyanophenyl 1:1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material Ig is 0.01, and the mol ratio of raw material Ig and ethyl diazoacetate II is 1:1.5.
Trans IIIg nuclear-magnetism:
1HNMR:δ8.35-8.15(m,4H),4.53(dd,J＝12,7Hz,1H),4,32(dd,J＝12,9Hz,1H),4.14(m,2H),1.90(ddd,J＝9,7,5Hz,1H),1.58(d,J＝5Hz,1H),1.30(t,J＝7Hz,3H),1.27(s,3H),1.26(s,3H)
Cis IIIg nuclear-magnetism:
1HNMR:δ8.35-8.15(m,4H),4.80(dd,J＝22,7Hz,1H),4.75(dd,J＝22,7,1Hz,1H),4.11(q,J＝7Hz,2H),1.65(d,J＝9Hz,1H),1.64(ddd,J＝9,7,7Hz,1H),1.35(s,3H),1.25(t,J＝7Hz,3H),1.24(s,3H)
Embodiment 1h
The preparation of intermediate III h:
Operation is with example Ia: wherein catalyzer is the cuprous complex compound with cyanophenyl 1:1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material Ih is 0.01, and the mol ratio of raw material Ih and ethyl diazoacetate II is 1:1.5.
Trans IIIh nuclear-magnetism:
1HNMR:δ8.85(td,J＝2,1Hz,1H),8.43(ddd,J＝8,4,1Hz,1H),8.38(ddd,J＝8,2,1Hz,1H),7.68(td,J＝8,1Hz,1H),4.53(dd,J＝12,7Hz,1H),4.33(dd,J＝12,8Hz,1H),4.16(m,2H),1.92(ddd,J＝8,7,5Hz,1H),1.59(d,J＝5Hz,1H),1.30(s,6H),1.28(t,J＝7Hz,3H)
Cis IIIh nuclear-magnetism:
1HNMR:δ8.85(td,J＝2,1Hz,1H),8.43(ddd,J＝8,4,1Hz,1H),8.38(ddd,J＝8,2,1Hz,1H),7.68(td,J＝8,1Hz,1H),4.81(dd,J＝18,7Hz,1H),4.77(dd,J＝18,6,1Hz,1H),4.11(m,2H),1.65(d,J＝9Hz,1H),1.64(ddd,J＝9,7,6Hz,1H),1.35(s,3H),1.28(t,J＝7Hz,3H),1.26(s,3H)
Embodiment 1i
The preparation of intermediate III i:
Operation is with example Ia: wherein catalyzer is the cuprous complex compound with cyanophenyl 1:1 of trifluoromethanesulfonic acid, and the weight ratio of catalyzer and raw material Ii is 0.01, and the mol ratio of raw material Ii and ethyl diazoacetate II is 1:1.5.
Trans IIIi nuclear-magnetism:
1HNMR:δ7.99(dt,J＝9,2Hz,2H),6.93(dt,J＝9,2Hz,2H),4.46(dd,J＝12,7Hz,1H),4.20(dd,J＝12,8Hz,1H),4.14(m,2H),3.87(s,3H),1.87(ddd,J＝8,7,5Hz,1H),1.52(d,J＝5Hz,1H),1.27(s,3H),1.26(t,J＝7Hz,3H),1.25(s,3H)
Cis IIIi nuclear-magnetism:
1HNMR:δ7.99(dt,J＝9,2Hz,2H),6.91(dt,J＝9,2Hz,2H),4.70(dd,J＝22,7Hz,1H),4.65(ddd,J＝22,6,2Hz,1H),4.11(m,2H),3.86(s,3H),1.62(d,J＝6Hz,1H),1.60(m,1H),1.34(s,3H),1.25(t,J＝7Hz,3H),1.22(s,3H)
Embodiment 2a
The preparation of intermediate IV:
Intermediate III (8.3g), water (9ml) mixes.Stirring is warming up to 50 DEG C, adds the aqueous sodium hydroxide solution (24.2g) of 28wt%.At 50 DEG C, be incubated 2 hours.Obtain the aqueous solution of intermediate compound IV (3-methylol-2,2-dimethyl ethylene-acetic acid).Be directly used in next step reaction.
Extract reaction solution 10g, be acidified to pH to 1, be incubated 2 hours, regulate pH value to 9, ethyl acetate extraction, is dried to obtain the interior ester products of cis.The remaining aqueous solution is regulated to pH value to 1, ethyl acetate extraction, the dry trans-compound IV that concentrates to obtain
Nuclear magnetic data is as follows:
Ester products in cis:
1H?NMR(400MHz,CDCI
3)1.16(s,3H),1.17(s,3H),1.93(d,1H,J＝6.3Hz),2.05(dd,1H,J＝8.7,3.1Hz),4.14(d,1H,J＝9.9Hz),4.35(dd,1H,J＝9.9,5.5Hz)。
Trans-compound IV:
1H?NMR(400MHz,CDCl
3)δ1.21(s,3H),1.26(s,3H),1.41(d,1H,J＝5.5Hz),1.79–1.63(m,1H),1.90(br,1H),3.67(d,J＝7.4Hz,2H),9.3-9.8(br,1H)。
Embodiment 2b
The preparation of intermediate IV:
Intermediate III b (10g), 6N hydrochloric acid (5ml), tetrahydrofuran (THF) (30ml) mixes.Stirring at room temperature 1 hour, after pressure reducing and steaming tetrahydrofuran (THF), adds the aqueous sodium hydroxide solution (40g) of 28wt%.At 50 DEG C, be incubated 2 hours.Obtain the aqueous solution of intermediate compound IV (3-methylol-2,2-dimethyl ethylene-acetic acid).Be directly used in next step reaction.
Extract reaction solution 10g, be acidified to pH to 1, be incubated 2 hours, regulate pH value to 9, ethyl acetate extraction, is dried to obtain the interior ester products of cis.The remaining aqueous solution is regulated to pH value to 1, ethyl acetate extraction, the dry trans-compound IV that concentrates to obtain
Nuclear magnetic data is with implementing 2a.
Embodiment 2c
The preparation of intermediate IV:
Operation embodiment 2b
Nuclear-magnetism is with implementing 2a.
Embodiment 2d
The preparation of intermediate IV:
Intermediate III d (12g), ethanol (100ml) mixes.Add 10%Pd-C catalyzer (1.0g), logical hydrogen to raw material disappears.Filter, ethanol is removed in decompression, stirs and is warming up to 50 DEG C, adds the aqueous sodium hydroxide solution (24.2g) of 28wt%.At 50 DEG C, be incubated 2 hours.Obtain the aqueous solution of intermediate compound IV (3-methylol-2,2-dimethyl ethylene-acetic acid).Be directly used in next step reaction.
Extract reaction solution 10g, be acidified to pH to 1, be incubated 2 hours, regulate pH value to 9, ethyl acetate extraction, is dried to obtain the interior ester products of cis.The remaining aqueous solution is regulated to pH value to 1, ethyl acetate extraction, the dry trans-compound IV that concentrates to obtain
Nuclear magnetic data is consistent with embodiment 2a.
Embodiment 2e
The preparation of intermediate IV:
Operation embodiment 2b
Nuclear-magnetism is with implementing 2a.
Embodiment 2e
The preparation of intermediate IV:
Operation embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 2f
The preparation of intermediate IV:
Operation embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 2h
The preparation of intermediate IV:
Operation embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 2i
The preparation of intermediate IV:
Operation embodiment 2a
Nuclear-magnetism is with implementing 2a.
Embodiment 3
The preparation of carane aldehydic acid lactone:
The aqueous solution that obtains intermediate compound IV in embodiment 2a-2i is raw material reaction liquid.
In the aqueous solution of the above-mentioned intermediate compound IV that cools to 5 DEG C, add 50% sulphur acid for adjusting pH to 8-10, add acetonitrile 5mL, 0.3 gram of Potassium Bromide.Add tetramethyl piperidine oxide compound 0.1g, the aqueous solution (cl content 10% approximately uses 20 grams) of the clorox of dropping 12%.
Be warmed up to 20-25 DEG C, continue to stir 30 minutes, reaction system is poured into the sodium sulfite aqueous solution of 0 DEG C, with salt acid for adjusting pH to 5, make to be extracted with ethyl acetate, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains carane aldehydic acid lactone 2g.
1H?NMR(300MHz,CDCI3)1.20(s,6H),2.10(s,2H),5.50(br?s,1H),5.13-5.87(m,1H)。
IR:Vmax(neat):3300,1720cm-1，MS:m/z?127(M-15)+and?67(100％)。
Embodiment 4
The preparation of card dragon acid:
The aqueous solution that obtains intermediate compound IV in embodiment 2a-2i is raw material reaction liquid.
In the aqueous solution of the above-mentioned intermediate compound IV that cools to 5 DEG C, add 50% sulphur acid for adjusting pH to 8-10, add acetonitrile 5mL, 0.3 gram of Potassium Bromide.Add tetramethyl piperidine oxide compound 0.1g, the aqueous solution (cl content 10% approximately uses 20 grams) of the clorox of dropping 12%.Stir 20 minutes.Regulate pH value to 4-7, drip 25% sodium chlorite aqueous solution 16g.Drip off rear stirring 2 hours.
Reaction system is poured into the sodium sulfite aqueous solution of 0 DEG C, with salt acid for adjusting pH to 1, made to be extracted with ethyl acetate, anhydrous sodium sulfate drying, removal of solvent under reduced pressure obtains the imperial sour 2g of card.
1H?NMR(300MHz,CD
3OD)；cis-isomer?1.25(s,3H),1.41(s,3H),1.95(s,2H)；trans-isomer8?1.31(s,6H),2.20(s,2H)。
Embodiment 5
The preparation of Caronic anhydride:
In reaction flask, add aceticanhydride 200ml, block imperial sour 100g, reflux 3 hours, after unnecessary aceticanhydride is removed in decompression, underpressure distillation obtains Caronic anhydride 70g, productive rate >80%.
m.p.:53-55℃。
1H?NMR(300MHz,CDCI
3)1.32(s,3H),1.41(s,3H).2.65(s,2H)。
Claims (11)
1. a synthetic method of blocking dragon acid, comprises the following steps:
1) taking the protected prenol of hydroxyl (I) as raw material; Two keys of raw material are carried out to addition reaction with the compound of formula II, obtain triatomic ring intermediate (III);
2) to the reaction that is hydrolyzed of the ethoxycarbonyl on triatomic ring intermediate (III), and deprotection base R, 3-methylol-2 obtained, 2-dimethyl ethylene-acetic acid (IV);
3) make 3-methylol-2,2-dimethyl ethylene-acetic acid is soluble in water, and regulating pH value is 8～10, then carries out oxidizing reaction; The condition of described oxidizing reaction is: at-5～15 DEG C, add acetonitrile, Potassium Bromide and tetramethyl piperidine oxide compound, and drip the aqueous solution of clorox, then stir 10～50min; Regulate again pH value to 4～7, drip the aqueous solution of Textone, after dropwising, react; Completely rear separation of oxidizing reaction obtains the acid of product card dragon;
Step 1) and step 2) reaction scheme as follows:
In formula: R is blocking group; R
1for optionally replacement or unsubstituted alkyl, optionally replacement or unsubstituted assorted alkyl, optionally replacement or unsubstituted cycloalkyl, optionally replacement or unsubstituted Heterocyclylalkyl, optionally replacement or unsubstituted aryl and optionally replacement or unsubstituted heteroaryl.
2. the synthetic method of card dragon as claimed in claim 1 acid, is characterized in that, R is selected from ester class protecting group, alkyl ether protecting group and silicon ethers protecting group.
3. the synthetic method of card dragon as claimed in claim 2 acid, is characterized in that, described ester class protecting group is selected from ethanoyl, benzoyl or substituted benzoyl; Described alkyl ether protecting group is selected from benzyl, triphenyl methane base or THP trtrahydropyranyl; Described silicon ethers protecting group is selected from trimethyl silicon based or the dimethyl tertiary butyl is silica-based.
4. the synthetic method of card dragon as claimed in claim 1 acid, is characterized in that R
1for methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl or benzyl.
5. the synthetic method of card dragon as claimed in claim 1 acid, it is characterized in that, step 1) described in addition reaction taking copper class catalyzer as catalyzer, reaction solvent is selected from one or more the mixing in ethylene dichloride, methylene dichloride or toluene, temperature of reaction is 25～110 DEG C.
6. the synthetic method of card dragon as claimed in claim 5 acid, it is characterized in that, described copper class catalyzer is selected from that metallic copper, cuprous chloride, cuprous bromide, cuprous iodide, trifluoromethanesulfonic acid are cuprous, one or more in copper sulfate, neutralized verdigris, fluoroform sulphonyl copper and cupric chloride.
7. the synthetic method of the dragon of the card as described in claim 5 or 6 acid, it is characterized in that, the mol ratio of described raw material and formula II compound is (0.5～1.5): 1, and the weight ratio of copper class catalyzer and raw material is (0.01～0.5): 1.
8. the synthetic method of card dragon as claimed in claim 1 acid, is characterized in that, tetramethyl piperidine oxide compound and 3-methylol-2, and the mass ratio of 2-dimethyl ethylene-acetic acid is (0.01～0.5): 1; Weight proportion between Potassium Bromide, tetramethyl piperidine oxide compound, the aqueous solution of clorox and the aqueous solution of Textone is 1:(0.1～0.5): (50～100): (30～100); Cl content in the aqueous solution of described aqueous sodium hypochlorite solution and Textone is respectively 5～15wt%.
9. the synthetic method of card dragon as claimed in claim 1 acid; it is characterized in that; described step 2) in; ethoxycarbonyl on triatomic ring intermediate (III) is hydrolyzed after reaction deprotection base; do not carry out aftertreatment; directly lowering the temperature and regulating its pH value is 8～10, then carries out follow-up oxidizing reaction.
10. a synthetic method for Caronic anhydride, comprises step: use the imperial acid of card to carry out ring-closure reaction and obtain product Caronic anhydride; Described card dragon acid prepares as the sour method of described Synthesis Card dragon arbitrary in claim 1-9 by adopting.
The synthetic method of 11. Caronic anhydrides as claimed in claim 10, is characterized in that, described ring-closure reaction, taking aceticanhydride as solvent, carries out under the reflux temperature of aceticanhydride, and the reaction times is 2～4h.
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