CN113061072A - Method for preparing 1-cyclopropyl naphthalene - Google Patents
Method for preparing 1-cyclopropyl naphthalene Download PDFInfo
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- CN113061072A CN113061072A CN202110339208.6A CN202110339208A CN113061072A CN 113061072 A CN113061072 A CN 113061072A CN 202110339208 A CN202110339208 A CN 202110339208A CN 113061072 A CN113061072 A CN 113061072A
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- 238000000034 method Methods 0.000 title claims abstract description 29
- VZZBXOLWBXJHEK-UHFFFAOYSA-N 1-cyclopropylnaphthalene Chemical compound C1CC1C1=CC=CC2=CC=CC=C12 VZZBXOLWBXJHEK-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- 229910052751 metal Inorganic materials 0.000 claims abstract description 9
- 239000002184 metal Substances 0.000 claims abstract description 9
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 64
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 54
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 36
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 18
- 239000003638 chemical reducing agent Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 238000006116 polymerization reaction Methods 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 8
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 7
- 239000012279 sodium borohydride Substances 0.000 claims description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 7
- DIKBFYAXUHHXCS-UHFFFAOYSA-N bromoform Chemical compound BrC(Br)Br DIKBFYAXUHHXCS-UHFFFAOYSA-N 0.000 claims description 6
- 239000003444 phase transfer catalyst Substances 0.000 claims description 6
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 229960001701 chloroform Drugs 0.000 claims description 5
- OKJPEAGHQZHRQV-UHFFFAOYSA-N iodoform Chemical compound IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 5
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N 1,4-Benzenediol Natural products OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 4
- QHPQWRBYOIRBIT-UHFFFAOYSA-N 4-tert-butylphenol Chemical compound CC(C)(C)C1=CC=C(O)C=C1 QHPQWRBYOIRBIT-UHFFFAOYSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 229950005228 bromoform Drugs 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- FMWLUWPQPKEARP-UHFFFAOYSA-N bromodichloromethane Chemical compound ClC(Cl)Br FMWLUWPQPKEARP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 125000000687 hydroquinonyl group Chemical group C1(O)=C(C=C(O)C=C1)* 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 2
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 8
- 229910000510 noble metal Inorganic materials 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- 230000009467 reduction Effects 0.000 abstract description 4
- 238000006722 reduction reaction Methods 0.000 abstract description 4
- QQLIGMASAVJVON-UHFFFAOYSA-N 1-naphthalen-1-ylethanone Chemical compound C1=CC=C2C(C(=O)C)=CC=CC2=C1 QQLIGMASAVJVON-UHFFFAOYSA-N 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000005695 dehalogenation reaction Methods 0.000 abstract description 2
- 230000018044 dehydration Effects 0.000 abstract description 2
- 238000006297 dehydration reaction Methods 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 229940126214 compound 3 Drugs 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 238000000926 separation method Methods 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- 238000001035 drying Methods 0.000 description 8
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 7
- 229940125782 compound 2 Drugs 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 229940125898 compound 5 Drugs 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000011031 large-scale manufacturing process Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- IGGDKDTUCAWDAN-UHFFFAOYSA-N 1-vinylnaphthalene Chemical compound C1=CC=C2C(C=C)=CC=CC2=C1 IGGDKDTUCAWDAN-UHFFFAOYSA-N 0.000 description 2
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 229940125907 SJ995973 Drugs 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- KTMKRRPZPWUYKK-UHFFFAOYSA-N methylboronic acid Chemical compound CB(O)O KTMKRRPZPWUYKK-UHFFFAOYSA-N 0.000 description 2
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005111 flow chemistry technique Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/26—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only halogen atoms as hetero-atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/20—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms
- C07C1/24—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from organic compounds containing only oxygen atoms as heteroatoms by elimination of water
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
-
- 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
- Y02P20/584—Recycling of catalysts
Abstract
The invention belongs to the technical field of organic synthesis, and particularly discloses a method for preparing 1-cyclopropyl naphthalene. The method adopts 1-acetonaphthone as a raw material, and can synthesize the 1-cyclopropyl naphthalene simply and conveniently through reduction, dehydration, cyclization, reduction and dehalogenation. The method has the advantages of cheap and easily obtained raw materials, no need of noble metal or dangerous organic metal reagents, low raw material cost, convenient production, environmental protection and safety, and is very suitable for industrial production. The method has the advantages of high yield in each step, less by-products and easy purification.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a method for preparing 1-cyclopropyl naphthalene.
Background
1-cyclopropyl naphthalene is an important organic molecular skeleton and widely exists in chemical raw materials and active molecules of medicines. At present, methods for synthesizing 1-cyclopropyl naphthalene are reported, and the following methods are mainly reported:
firstly, the catalyst is prepared by the coupling reaction of cyclopropyl boronic acid and halogenated naphthalene under a palladium catalyst, the reaction equation is as follows, and the method needs to use noble metal and methyl boronic acid, has high cost and is not beneficial to industrial large-scale production;
bis, cyclopropyl metal reagents (e.g., lithium, magnesium) and halonaphthalenes are prepared by palladium or nickel catalyzed coupling. The method also uses noble metals and high-activity metal reagents, and is not beneficial to industrial large-scale production.
Thirdly, the 1-cyclopropyl naphthalene is obtained by cyclization of the 1-vinylnaphthalene and the methylene dihalide under the action of strong alkali tert-butyl magnesium chloride, the reaction equation is as follows, and the method uses a high-activity metal reagent, and is not beneficial to industrial large-scale production.
In conclusion, the existing methods use either noble metals and expensive methylboronic acid or high-activity metal reagents, so that the production cost is high, the operation is complex, the risk is extremely high, and the industrial large-scale production is not facilitated. Meanwhile, due to a large amount of metal residues and a large amount of solid waste, great pressure is brought to the purification and environmental protection of the compounds.
Therefore, the development of a new method for preparing 1-cyclopropyl naphthalene is more suitable for industrial production and has important significance.
Disclosure of Invention
The invention solves the technical problem of providing the method for preparing the 1-cyclopropyl naphthalene, and the method has the advantages of cheap and easily obtained raw materials, no need of noble metals, convenient production, environmental protection, safety and easy purification.
In order to solve the technical problems, the invention adopts the following technical scheme: a method for preparing 1-cyclopropyl naphthalene, the reaction equation is as follows:
wherein, X is selected from halogen, preferably any one of chlorine, bromine and iodine;
the preparation method comprises the following steps:
the first step is as follows: reducing the compound shown in the formula 1 by using a reducing agent 1 to obtain a compound shown in a formula 2;
the second step is that: dehydrating the compound shown in the formula 2 under the action of a catalyst and a polymerization inhibitor to obtain a compound shown in a formula 3;
the third step: cyclizing the compound shown in the formula 3 under the action of a cyclizing reagent and a base to synthesize a compound shown in a formula 4;
the fourth step: reducing the compound shown in the formula 4 under the action of a reducing agent 2 and alkali to obtain a compound 1-cyclopropyl naphthalene shown in a formula 5;
wherein the reducing agent 1 is selected from any one or a mixture of several of sodium borohydride, lithium aluminum hydride and diisobutyl aluminum hydride;
the catalyst is one or a mixture of several of methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid and sulfuric acid;
the polymerization inhibitor is hydroquinone and/or p-tert-butylphenol;
the cyclization reagent is any one or a mixture of more of trichloromethane, bromodichloromethane, tribromomethane and iodomethane;
the reducing agent 2 is any one or a mixture of several of metal copper, iron, zinc, lithium, sodium, potassium and aluminum;
the base is an inorganic base.
As a preferred embodiment of the present invention, the reaction solvent in the first step is any one of methanol, ethanol, and isopropanol, preferably methanol;
the reducing agent 1 is sodium borohydride;
the molar ratio of the compound shown in the formula 1 to the reducing agent 1 is 1 (0.5-1), and preferably 1 (0.7-0.9).
As a preferred embodiment of the present invention, the reaction solvent in the second step is toluene, xylene, preferably toluene;
the catalyst is p-toluenesulfonic acid;
the reaction molar ratio of the compound shown in the formula 2 to the catalyst is (10-3): 1, preferably (5-6): 1; and/or the using amount of the polymerization inhibitor is 0.02-0.03% of the mole number of the compound shown in the formula 2.
Further preferably, the second step of reaction is carried out in a pipeline, the compound shown in the formula 2, a catalyst and a polymerization inhibitor are added into a solvent to be uniformly mixed, then the mixture is pumped into the reaction pipeline and is reacted when flowing through the reaction pipeline, and the mixture flows out of the reaction pipeline and is cooled to room temperature to obtain the compound shown in the formula 3; the temperature of the reaction pipeline is 120-140 ℃, and the further optimization is 130 ℃.
In order to avoid the self-polymerization of the compound represented by formula 3 at high temperature, a polymerization inhibitor is added during the reaction, so that the compound 3 can be stably present in the reaction system for a short time. Meanwhile, a synthesis method of pipeline flow chemistry is adopted, so that the retention time of the generated compound 3 at high temperature is shortened as much as possible, the effect that the compound 3 is almost free of polymerization is achieved, and the reaction yield is improved.
As a preferred embodiment of the present invention, in the third step, the base used is sodium hydroxide and/or potassium hydroxide, preferably sodium hydroxide;
the reaction solvent is toluene;
the reaction molar ratio of the compound shown in the formula 3 to the cyclization agent and the base is 1: (2-6): (4-6).
Further preferably, in the third step of reaction, in order to improve the reaction yield, a phase transfer catalyst is further added to the reaction system, the phase transfer catalyst is any one of 18-crown-6 ether, tetrabutylammonium fluoride, tetrabutylammonium chloride and tetrabutylammonium bromide, and the dosage of the phase transfer catalyst is preferably 8-15% of the weight of the compound represented by formula 3.
In the fourth step, as a preferred embodiment of the invention, the reducing agent 2 used in the reaction is metallic zinc powder;
the alkali is sodium hydroxide and/or potassium hydroxide, preferably sodium hydroxide;
the reaction solvent is any one of acetonitrile, propionitrile, methanol, ethanol and isopropanol;
the reaction molar ratio of the compound shown as the formula 4 to the reducing agent 2 and the base is 1: (7-10): (14-18).
The invention also provides 1-cyclopropyl naphthalene prepared by the method.
The invention has the following beneficial effects: the invention provides a new method for preparing 1-cyclopropyl naphthalene, which adopts 1-acetonaphthalene as a raw material to synthesize the 1-cyclopropyl naphthalene simply and conveniently through four steps of reduction, dehydration, cyclization and reduction dehalogenation. The method has the advantages of cheap and easily obtained raw materials, no need of noble metal or dangerous organic metal reagents, low raw material cost, convenient production, environmental protection and safety, and is very suitable for industrial production. The method has high yield of each step and few byproducts, for example, the intermediate product 1-vinylnaphthalene is conveniently synthesized by a pipeline flow chemical mode, the defect that the compound 3 is easy to polymerize by itself to generate side reaction is effectively avoided, the reaction yield is further improved, and the reaction product has the advantage of easy purification and has important significance for industrial production.
Detailed Description
The technical solution of the present invention will be described in detail by examples.
Example 1
The reaction equation in this example is:
is prepared by the following steps:
(1) 1kg of sodium borohydride is added in portions to a mixture of 5.53kg of compound 1 and 20kg of methanol, the mixture is stirred for 2 hours after the addition is finished, and water is added to quench the reaction after the reaction is finished by HPLC detection. Then, the mixture is extracted by ethyl acetate and saturated ammonium chloride, the water phase is extracted by ethyl acetate for three times, the organic phases are combined, dried and spin-dried to obtain 5.53kg of the compound 2, the GC purity is more than 99 percent, and the yield is 98.9 percent.
The assay data for compound 2 was:1H NMR(CDCl3,400MHz):δ＝1.68(d,J＝6.4Hz,3H),5.68(q,J＝6.5Hz,1H),7.43-7.57(m,3H),7.68(d,J＝7.0Hz,1H),7.78(d,J＝8.2Hz,1H),7.83 7.93(m,1H),8.12(d,J＝7.9Hz,1H)。
(2) 5.53kg of compound 2, 1kg of p-toluenesulfonic acid, 1g of hydroquinone and 80L of toluene are uniformly mixed, and then the mixture is pumped into a reaction coil heated to 130 ℃ through a diaphragm pump, so that the reaction mixture flows through the reaction coil, reacts while flowing through a reaction pipeline, and is immediately cooled to room temperature through a condensing device after flowing out of the reaction pipeline. The reaction solution was collected, and 20L of water was added to remove the catalyst p-toluenesulfonic acid. The organic phase was then concentrated by drying to give 4.9kg of compound 3, with a GC purity of greater than 95% and a yield of 98.9%.
The assay data for compound 3 was:1H NMR(CDCl3,400MHz):δ＝8.13(d，J＝7.89，1H)，7.87-7.78(m，2H)，7.63(d，J＝7.12，1H)，7.54-7.44(m，4H)，5.80(dd，J＝17.29，J＝1.45，1H)，5.49(dd，J＝10.92，J＝1.44，1H)。
(3) 2kg of sodium hydroxide was added in portions to a mixture of 1.6kg of compound 3, 5kg of chloroform, 0.14kg of 18-crown-6 ether and 50L of toluene at room temperature, and after the addition, the reaction was started and was detected to be complete by HPLC. The insoluble matter was removed by filtration, and 20L of saturated brine was added thereto, followed by stirring for 1 hour, standing and liquid separation. The organic phase was concentrated to give 1.97kg of compound 4a with a GC purity of greater than 95% and a yield of 80.0%.
The assay data for compound 4a was:1H NMR(CDCl3,400MHz):δ＝8.27(d，J＝8.4，1H)，7.95(d，J＝8，1H)，7.88(d，J＝8，1H)，7.71-7.67(m，2H)，7.62-7.44(m，1H)，7.29(d，J＝6，1H)，3.31-3.27(m，1H)，2.20-2.07(m，2H)。
(4) 6kg of sodium hydroxide are added in portions to a mixture of 2.2kg of compound 4a, 5kg of zinc dust and 15kg of acetonitrile under reflux, and after the addition is complete, stirring is continued until the HPLC starting material disappears. Cooling, dripping 10kg of acetic acid, stirring for 1 hour after dripping, filtering to remove insoluble substances, and concentrating. Petroleum ether and saturated brine were added to the mixture to conduct liquid separation extraction. The organic phase was concentrated by drying to give an oily liquid. This oily liquid was subjected to distillation under reduced pressure to give 1.23kg of Compound 5, GC purity > 95%, yield 78.5%.
The assay data for compound 3 was:1H NMR(CDCl3,400MHz):δ＝8.40(d,J＝8.3Hz,1H),7.80-6.90(m,6H),1.80(m,1H),1.05(m,2H),0.78(m,2H)。
example 2
The reaction equation in this example is:
is prepared by the following steps:
(1) adding 1kg of sodium borohydride into a mixture of 5.53kg of compound 1 and 20kg of methanol in batches, stirring for 2 hours after the addition is finished, adding water to quench the reaction after the HPLC detection reaction is finished, and adding ethyl acetate and saturated ammonium chloride for liquid separation and extraction. The aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, dried and spun to give 5.53kg of compound 2, with a GC purity of greater than 99% and a yield of 98.9%.
(2) 5.53kg of compound 2, 1kg of p-toluenesulfonic acid, 1g of p-tert-butylphenol and 80L of toluene were uniformly mixed, and the mixture was pumped into a reaction coil heated to 130 ℃ by a diaphragm pump, so that the reaction mixture flowed through the reaction coil and reacted while flowing through a reaction pipe, and the reaction mixture was immediately cooled to room temperature by a condensing device after flowing out of the reaction pipe. The reaction solution was collected, and 20L of water was added to remove the catalyst p-toluenesulfonic acid. The organic phase was then concentrated by drying to give 4.8kg of compound 3, with a GC purity of greater than 95% and a yield of 96.9%.
(3) 2kg of sodium hydroxide was added in portions to a mixture of 1.6kg of compound 3, 5kg of chloroform, 0.2kg of tetrabutylammonium chloride and 50L of toluene at room temperature, and after the addition, the reaction was carried out and detected by HPLC until the reaction was completed. The insoluble matter was removed by filtration, and 20L of saturated brine was added thereto, followed by stirring for 1 hour, standing and liquid separation. The organic phase was concentrated to give 1.86kg of compound 4a with a GC purity of greater than 95% and a yield of 75.5%.
(4) 6kg of sodium hydroxide are added in portions to a mixture of 2.2kg of compound 4a, 5kg of zinc powder and 15kg of ethanol under reflux, and after the addition, stirring is continued until the HPLC starting material disappears. Cooling, dripping 10kg of acetic acid, stirring for 1 hour after dripping, filtering to remove insoluble substances, and concentrating. Petroleum ether and saturated brine were added to the mixture to conduct liquid separation extraction. The organic phase was concentrated by drying to give an oily liquid. This oily liquid was subjected to distillation under reduced pressure to give 1.4kg of Compound 5, GC purity > 95%, yield 89.4%.
Example 3
The reaction equation in this embodiment is:
is prepared by the following steps:
(1) 1kg of sodium borohydride is added in portions to a mixture of 5.53kg of compound 1 and 20kg of methanol, the mixture is stirred for 2 hours after the addition is finished, and water is added to quench the reaction after the reaction is finished by HPLC detection. Adding ethyl acetate and saturated ammonium chloride for liquid separation and extraction. The aqueous phase was extracted three times with ethyl acetate, the organic phases were combined, dried and spun to give 5.53kg of compound 2, with a GC purity of greater than 99% and a yield of 98.9%.
(2) 5.53kg of compound 2, 1kg of p-toluenesulfonic acid, 1g of p-tert-butylphenol and 80L of toluene were uniformly mixed, and the mixture was pumped into a reaction coil heated to 130 ℃ by a diaphragm pump, so that the reaction mixture flowed through the reaction coil and reacted while flowing through a reaction pipe, and the reaction mixture was immediately cooled to room temperature by a condensing device after flowing out of the reaction pipe. The reaction solution was collected, and 20L of water was added to remove the catalyst p-toluenesulfonic acid. The organic phase was then concentrated by drying to give 4.8kg of compound 3, with a GC purity of greater than 95% and a yield of 96.9%.
(3) 2kg of sodium hydroxide was added to a mixture of 1.6kg of compound 3, 5kg of chloroform, 0.2kg of tetrabutylammonium chloride and 50L of toluene in portions at room temperature, and after the addition, the reaction was completed by HPLC detection. The insoluble matter was removed by filtration, and 20L of saturated brine was added thereto, followed by stirring for 1 hour, standing and liquid separation. The organic phase was concentrated to give 1.86kg of compound 4a with a GC purity of greater than 95% and a yield of 75.5%.
(4) 6kg of sodium hydroxide are added in portions to a mixture of 2.2kg of compound 4a, 5kg of zinc dust and 15kg of methanol under reflux, and after the addition, stirring is continued until the HPLC starting material disappears. Cooling, dripping 10kg of acetic acid, stirring for 1 hour after dripping, filtering to remove insoluble substances, and concentrating. Petroleum ether and saturated brine were added to the mixture to conduct liquid separation extraction. The organic phase was concentrated by drying to give an oily liquid. This oily liquid was subjected to distillation under reduced pressure to give 1.1kg of Compound 5, GC purity > 95%, yield 70.2%.
Example 4
The reaction equation in this embodiment is:
synthesized by the following steps:
synthesis of Compounds 2 and 3 prepared according to example 1.
Synthesis of compound 4 b: 2kg of sodium hydroxide were added in portions to a mixture of 1.6kg of compound 3, 13.1kg of tribromomethane, 0.14kg of 18-crown-6 ether and 50L of toluene at room temperature, and after the addition, the reaction was carried out and checked by HPLC until the reaction was completed. The insoluble matter was removed by filtration, and 20L of saturated brine was added thereto, followed by stirring for 1 hour, standing and liquid separation. The organic phase was concentrated to yield 3.49kg of compound 4 b. The GC purity is greater than 95% and the yield is 80%.
Synthesis of Compound 5: 6kg of sodium hydroxide are added in portions to a mixture of 3kg of compound 4b, 5kg of zinc dust and 15kg of methanol under reflux, and after the addition, stirring is continued until the HPLC starting material disappears. Cooling, dripping 10kg of acetic acid, stirring for 1 hour after dripping, filtering to remove insoluble substances, and concentrating. Petroleum ether and saturated brine were added to the mixture to conduct liquid separation extraction. The organic phase was concentrated by drying to give an oily liquid. This oily liquid was subjected to distillation under reduced pressure to give 1.15kg of Compound 5, GC purity > 95%, yield 73.2%.
Example 5
The reaction equation in this embodiment is:
synthesized by the following steps:
synthesis of Compounds 2 and 3 prepared according to example 1.
Synthesis of compound 4 c: 2kg of sodium hydroxide were added in portions to a mixture of 1.6kg of Compound 3, 20.4kg of triiodomethane, 0.14kg of 18-crown-6 ether and 50L of toluene, and after the addition, the reaction was complete and checked by HPLC. The insoluble matter was removed by filtration, and 20L of saturated brine was added thereto, followed by stirring for 1 hour, standing and liquid separation. The organic phase was concentrated to give 1.86kg of compound 4c with a GC purity of more than 95%.
Synthesis of Compound 5: 6kg of sodium hydroxide are added in portions to a mixture of 3.9kg of compound 4c, 5kg of zinc dust and 15kg of methanol under reflux, and after the addition, stirring is continued until the HPLC starting material disappears. Cooling, dripping 10kg of acetic acid, stirring for 1 hour after dripping, filtering to remove insoluble substances, and concentrating. Petroleum ether and saturated brine were added to the mixture to conduct liquid separation extraction. The organic phase was concentrated by drying to give an oily liquid. This oily liquid was subjected to distillation under reduced pressure to give 1.05kg of Compound 5, a GC purity of more than 95%, and a yield of 67.0%.
The above description is only an example of the present invention, and is not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention in the specification or other related fields directly or indirectly are included in the scope of the present invention.
Claims (8)
1. A method for preparing 1-cyclopropyl naphthalene is characterized in that a reaction equation is as follows:
wherein, X is selected from halogen, preferably any one of chlorine, bromine and iodine;
the preparation method comprises the following steps:
the first step is as follows: reducing the compound shown in the formula 1 by using a reducing agent 1 to obtain a compound shown in a formula 2;
the second step is that: dehydrating the compound shown in the formula 2 under the action of a catalyst and a polymerization inhibitor to obtain a compound shown in a formula 3;
the third step: cyclizing the compound shown in the formula 3 under the action of a cyclizing reagent and a base to synthesize a compound shown in a formula 4;
the fourth step: reducing the compound shown in the formula 4 under the action of a reducing agent 2 and alkali to obtain a compound 1-cyclopropyl naphthalene shown in a formula 5;
wherein the reducing agent 1 is selected from any one or a mixture of several of sodium borohydride, lithium aluminum hydride and diisobutyl aluminum hydride;
the catalyst is one or a mixture of several of methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid and sulfuric acid;
the polymerization inhibitor is hydroquinone and/or p-tert-butylphenol;
the cyclization reagent is any one or a mixture of more of trichloromethane, bromodichloromethane, tribromomethane and triiodomethane;
the reducing agent 2 is any one or a mixture of several of metal copper, iron, zinc, lithium, sodium, potassium and aluminum;
the base is an inorganic base.
2. The method according to claim 1, wherein the reaction solvent in the first step is any one of methanol, ethanol, isopropanol, preferably methanol; and/or the reducing agent 1 is sodium borohydride; and/or the molar ratio of the compound shown in the formula 1 to the reducing agent 1 is 1 (0.5-1), preferably 1 (0.7-0.9).
3. The process according to claim 1 or 2, characterized in that the reaction solvent in the second step is toluene, xylene, preferably toluene; and/or the catalyst is p-toluenesulfonic acid; and/or the reaction molar ratio of the compound shown in the formula 2 to the catalyst is (10-3): 1, preferably (5-6): 1; and/or the using amount of the polymerization inhibitor is 0.02-0.03% of the mole number of the compound shown in the formula 2.
4. The method as claimed in claim 3, wherein the second step of reaction is carried out in a pipeline, the compound represented by formula 2, the catalyst and the polymerization inhibitor are added into the solvent and uniformly mixed, then the mixture is pumped into the reaction pipeline and reacts while flowing through the reaction pipeline, and the mixture flows out of the reaction pipeline and is cooled to room temperature to obtain the compound represented by formula 3; the temperature of the reaction pipeline is 120-140 ℃.
5. A process according to claim 4, characterized in that in the third step, the base used is sodium hydroxide and/or potassium hydroxide, preferably sodium hydroxide; and/or the reaction solvent is toluene; and/or the reaction molar ratio of the compound shown in the formula 3 to the cyclization reagent and the base is 1: (2-6): (4-6).
6. The method according to claim 5, wherein in the third reaction step, a phase transfer catalyst is further added to the reaction system, the phase transfer catalyst is any one of 18-crown-6 ether, tetrabutylammonium fluoride, tetrabutylammonium chloride and tetrabutylammonium bromide, and preferably the amount of the phase transfer catalyst is 8-15% of the weight of the compound represented by formula 3.
7. The method as claimed in claim 5 or 6, wherein in the fourth step, the reducing agent 2 used for the reaction is metallic zinc powder; and/or, the alkali is sodium hydroxide and/or potassium hydroxide, preferably sodium hydroxide; and/or the reaction solvent is any one of acetonitrile, propionitrile, methanol, ethanol and isopropanol; and/or the reaction molar ratio of the compound shown in the formula 4 to the reducing agent 2 and the base is 1: (7-10): (14-18).
8. 1-cyclopropylnaphthalene prepared by the process of any one of claims 1 to 7.
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