CN115385784B - Preparation method of 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone - Google Patents
Preparation method of 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 82
- 239000003054 catalyst Substances 0.000 claims abstract description 40
- -1 alpha-hydroxy p-chlorobenzyl phosphonate Chemical compound 0.000 claims abstract description 24
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229940126214 compound 3 Drugs 0.000 claims abstract description 17
- HVCFCNAITDHQFX-UHFFFAOYSA-N 1-cyclopropylethanone Chemical compound CC(=O)C1CC1 HVCFCNAITDHQFX-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 230000002378 acidificating effect Effects 0.000 claims abstract description 5
- LRWCURGZPQWMRG-UHFFFAOYSA-N 1-(4-chlorophenyl)-2-cyclopropylpropan-1-one Chemical compound C=1C=C(Cl)C=CC=1C(=O)C(C)C1CC1 LRWCURGZPQWMRG-UHFFFAOYSA-N 0.000 claims description 81
- 150000001875 compounds Chemical class 0.000 claims description 31
- SFLXUZPXEWWQNH-UHFFFAOYSA-K tetrabutylazanium;tribromide Chemical compound [Br-].[Br-].[Br-].CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC SFLXUZPXEWWQNH-UHFFFAOYSA-K 0.000 claims description 28
- 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 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- 239000002585 base Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 9
- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical compound [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 5
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims 1
- 230000000171 quenching effect Effects 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 abstract description 19
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000007062 hydrolysis Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- 230000000052 comparative effect Effects 0.000 description 15
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 9
- 229940125782 compound 2 Drugs 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 239000000047 product Substances 0.000 description 6
- UFNOUKDBUJZYDE-UHFFFAOYSA-N 2-(4-chlorophenyl)-3-cyclopropyl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol Chemical compound C1=NC=NN1CC(O)(C=1C=CC(Cl)=CC=1)C(C)C1CC1 UFNOUKDBUJZYDE-UHFFFAOYSA-N 0.000 description 5
- 239000005757 Cyproconazole Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 239000003899 bactericide agent Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 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
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- RIQJHXWKWXDLFM-UHFFFAOYSA-N (4-chlorophenyl)-diethoxyphosphorylmethanol Chemical compound CCOP(=O)(OCC)C(O)C1=CC=C(Cl)C=C1 RIQJHXWKWXDLFM-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/42—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by hydrolysis
-
- 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
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
-
- 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
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone, which comprises the following steps: reacting alpha-hydroxy p-chlorobenzyl phosphonate and 2, 3-dihydrofuran in the presence of a catalyst and a solvent to obtain diethyl ((4-chlorophenyl) ((tetrahydrofuran-2-yl) oxy) methyl) phosphonate, and reacting the diethyl ((4-chlorophenyl) ((tetrahydrofuran-2-yl) oxy) methyl) phosphonate with cyclopropylmethyl ketone to obtain a compound 3; compound 3 undergoes hydrolysis under acidic conditions. The invention takes alpha-hydroxy p-chlorobenzyl phosphonate as raw material, 2, 3-dihydrofuran as protecting group, and combines specific catalyst to prepare 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone, which improves reaction selectivity and obviously improves reaction yield and product purity, operation is safer and more environment-friendly, the purity of the prepared 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone is up to 98%, the prepared 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone can be directly used for subsequent reaction, and the total yield of three steps is more than 85%, and the highest total yield of three steps can be up to 95%.
Description
Technical Field
The invention relates to a preparation method of a bactericide cyproconazole intermediate, in particular to a preparation method of 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone, belonging to the field of preparation of cyproconazole intermediates.
Background
Cyproconazole (cyproconazole) is a triazole bactericide developed by the company san dozag in switzerland, is a systemic bactericide, has protective, therapeutic and virus-eradicating effects, and is widely applied to western europe and north america. 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone is a key intermediate for the synthesis of cyproconazole. At present, various methods for preparing 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone have been reported.
Patent document CN106883266a discloses a preparation route using α -hydroxy p-chlorobenzyl phosphonate and cyclopropylmethyl ketone as raw materials, dihydropyran as hydroxy protecting group, p-toluenesulfonic acid as catalyst, and obtaining 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone by adding protecting group, condensing and removing protecting group. The total yield of the three-step reaction of the route is only 80%, firstly, the selectivity of the protective group dihydropyran in the reaction is poor, secondly, the p-toluenesulfonic acid catalyst is strong acid, which is easy to damage reaction substrates, further, the reaction yield is reduced, and the industrial mass production is not facilitated.
Patent document CN107285998A discloses that p-chlorobenzaldehyde is taken as a starting material, benzyl alcohol or a derivative thereof is taken as a hydroxyl protecting group, two molecules of protecting groups are combined after an acetal reaction, one molecule of protecting groups is subjected to a phosphonation reaction to obtain alpha-benzyloxy p-chlorobenzyl phosphonate, and 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone is obtained through condensation and acidification hydrolysis reactions. The route combines two protecting groups in the acetal reaction, and when the phosphonate ester molecules are generated by catalysis, one molecule of protecting group needs to be selectively removed, the selectivity is poor, and the product yield is easy to influence. In addition, the lithium catalyst used in the route condensation reaction has great harm to the environment and human body, and is not suitable for industrial production.
In addition, other prior art reports that the dihydropyran or benzyl is adopted as a protecting group to protect hydroxyl for condensation reaction, and p-toluenesulfonic acid or lithium catalyst is adopted for condensation reaction, and the problems of poor atom economy, low reaction yield, great operation hazard and the like of the methods exist in different degrees, so that the method needs to be improved.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defects of the prior art and providing a preparation method of 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone, which has high yield, safety and environmental protection and is more suitable for industrial production.
In order to solve the technical problems, the technical scheme adopted by the invention comprises the following steps:
a process for the preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone comprising:
(1) Reacting alpha-hydroxy p-chlorobenzyl phosphonate and 2, 3-dihydrofuran in the presence of a catalyst and a solvent to obtain diethyl ((4-chlorophenyl) ((tetrahydrofuran-2-yl) oxy) methyl) phosphonate (compound 2);
(2) Diethyl ((4-chlorophenyl) ((tetrahydrofuran-2-yl) oxy) methyl) phosphonate (compound 2) and cyclopropylmethyl ketone are reacted in the presence of a base and a solvent to give compound 3;
(3) Carrying out hydrolysis reaction on the compound 3 under an acidic condition to obtain 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone (namely, a compound 4);
as a preferred embodiment of the present invention, it is preferred that the molar ratio of the α -hydroxy p-chlorobenzyl phosphonate, 2, 3-dihydrofuran and catalyst in step (1) is 1:1.0 to 2.0:0.01 to 1; wherein the catalyst can be any one or any combination of more than one of tetrabutylammonium tribromide, pyridine p-toluenesulfonate (PPTS), hydrogen fluoride pyridine or hydrogen fluoride triethylamine; preferably, the catalyst consists of tetrabutylammonium tribromide and pyridinium p-toluenesulfonate, and the molar ratio of tetrabutylammonium tribromide to pyridinium p-toluenesulfonate is preferably 1: (2-6), most preferably 1:4, a step of; alternatively, the catalyst is composed of tetrabutylammonium tribromide and hydrogen fluoride, and the molar ratio of tetrabutylammonium tribromide to hydrogen fluoride is preferably 1: (2-6), most preferably 1:3, a step of; alternatively, the catalyst is composed of tetrabutylammonium tribromide and triethylamine hydrogen fluoride, and the molar ratio of tetrabutylammonium tribromide to triethylamine hydrogen fluoride is preferably 1: (2-6), most preferably 1:2.
experiments show that the reaction yield is over 85 percent by taking dihydrofuran as a protecting group and combining para-toluenesulfonic acid pyridinium as a catalyst, tetrabutylammonium tribromide is additionally added as the catalyst, the reaction yield is remarkably improved, and particularly when the molar ratio of the added tetrabutylammonium tribromide to PPTS is 1:4, the reaction yield is up to 95 percent.
As a preferred embodiment of the present invention, the reaction conditions described in step (1) are preferably: reacting for 1-8 hours at the temperature of 0-25 ℃.
As a preferred embodiment of the present invention, the reaction in step (1) is completed further comprising a post-treatment step of: the reaction solution after the reaction is finished is saturated NaHCO 3 And saturated NaCl solution, and drying and concentrating the organic phase to obtain diethyl ((4-chlorophenyl) ((tetrahydrofuran-2-yl) oxy) methyl) phosphonate.
As a preferred embodiment of the present invention, the molar ratio of diethyl ((4-chlorophenyl) ((tetrahydrofuran-2-yl) oxy) methyl) phosphonate, cyclopropylmethyl ketone and base fed in step (2) is preferably 1:1.0 to 2.0:1.0 to 2.0; wherein the alkali comprises, but is not limited to, any one or more of lithium diisopropylamide, n-butyllithium, sodium amide or sodium tert-butoxide, and the mixture is obtained by combining the above materials according to any proportion; the reaction conditions are preferably: reacting for 1-10 hours at the temperature of minus 78-0 ℃; more preferably, the alkali and the cyclopropyl methyl ketone are added at the temperature of minus 78 ℃ to 0 ℃, and the reaction is carried out for 2 to 8 hours at the temperature of minus 40 ℃ to 0 ℃ after the addition is finished.
As a preferred embodiment of the present invention, the reaction in step (2) is further followed by a post-treatment comprising: after the reaction is finished, water is added for extraction, and the mixture is concentrated to obtain the compound 3.
As a preferred embodiment of the present invention, the molar ratio of compound 3 to acid in step (3) is preferably 1:1.0 to 2.0.
As a preferred embodiment of the invention, the hydrolysis reaction in the step (3) is to dissolve the compound 3 in a solvent, add a catalyst, add an acid dropwise, and then carry out hydrolysis reaction for 0.5 to 1.2 hours under an acidic condition of 0 to 60 ℃ after the addition is completed; wherein the acid includes, but is not limited to, any one or a combination of more than one of acetic acid, hydrochloric acid, p-toluenesulfonic acid or sulfuric acid.
As a preferred embodiment of the present invention, the reaction of step (3) is completed further comprising a post-treatment step of: after the reaction is finished, the reaction solution is concentrated, separated and purified to obtain the 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone.
The solvent in the present invention includes, but is not limited to, any one or any combination of more than one of methylene chloride, toluene, tetrahydrofuran or 1, 2-dichloroethane.
The inventor discovers that the hydroxyl activity of the reaction raw material alpha-hydroxy p-chlorobenzyl phosphonate is high at the double bond position, and side reaction is easy to occur, so that when the reaction is carried out with cyclopropyl methyl ketone, a proper hydroxyl protecting group needs to be selected, the side reaction is avoided, and the reaction efficiency is further improved. When the hydroxyl protecting group is selected, on one hand, the steric effect and the electronic effect of the reaction materials, such as the steric hindrance, the electron cloud density, the atomic electronegativity and the like, should be considered. On the other hand, the addition of protecting groups should be avoided from affecting the reaction at other sites. In addition, the difficulty of removing the hydroxyl protecting group is considered.
According to the invention, alpha-hydroxy p-chlorobenzyl phosphonate is used as a raw material, and dihydrofuran is used as a protecting group, compared with the prior art that dihydropyran is used as a protecting group, the addition of the dihydrofuran is easier to combine with the hydroxy group in the raw material for protection, the subsequent condensation reaction with cyclopropyl methyl ketone is not influenced, and the protection is easier to remove from reactants, so that the reaction rate and selectivity are improved, and the comprehensive reaction yield is greatly improved to more than 80%; meanwhile, the invention takes the pyridine p-toluenesulfonate, the hydrogen fluoride pyridine or the hydrogen fluoride triethylamine as the catalyst, compared with the addition of the p-toluenesulfonic acid, the reaction substrate is milder, and the side reactions such as decomposition, excessive oxidation and the like of reactants under the strong acid environment are avoided. Furthermore, the inventors have found that if a small amount of tetrabutylammonium tribromide is added, the reaction rate can be further increased, and a possible mechanism is that a small amount of tetrabutylammonium tribromide reacts with alcohol, and the resulting hydrogen bromide molecules catalyze the reaction.
The invention takes the alpha-hydroxy p-chlorobenzyl phosphonate as the raw material, takes the 2, 3-dihydrofuran as the protecting group, and simultaneously combines a specific catalyst to prepare the 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone, thereby having better effect, higher product purity, higher reaction yield and safer and more environment-friendly operation. The purity of the finally prepared 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone is high, the content is up to 98%, the method can be directly used for subsequent reactions, and the total yield of three steps is above 85%, and the highest yield can be up to 95%.
Drawings
FIG. 1A scheme of the process synthesis of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone of the present invention.
FIG. 2 is a nuclear magnetic resonance spectrum of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone prepared in example 1 of the present invention.
FIG. 3 is a nuclear magnetic resonance spectrum of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone prepared in example 1 of the present invention.
Detailed Description
The invention will be further described with reference to specific embodiments, and advantages and features of the invention will become apparent from the description. It should be understood that the embodiments described are exemplary only and should not be construed as limiting the scope of the invention in any way. It will be understood by those skilled in the art that various changes and substitutions can be made in the details and form of the technical solution of the present invention without departing from the spirit and scope of the invention, but these changes and substitutions fall within the scope of the present invention.
1 HNMR refers to nuclear magnetic resonance hydrogen spectroscopy, and all chromatographic contents are based on gas chromatography normalization analytical data.
Example 11 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
(1) Diethyl ((4-chlorophenyl) (hydroxy) methyl) phosphonate (compound 1) (27.88 g,100.0 mmol) was dissolved in 200mL anhydrous dichloromethane in a 500mL round bottom flaskAfter that, dihydrofuran (7.71 g,110.0 mmol) was added to obtain a mixture, the mixture was cooled to 0℃and the catalyst pyridine p-toluenesulfonate (2.51 g,10.0 mmol) was added under stirring, the reaction was gradually brought to room temperature and stirred for 3 to 5 hours. TLC monitoring of complete conversion of the starting material followed by successive passes of saturated NaHCO 3 And saturated NaCl washing. The organic phase was dried over anhydrous sodium sulfate and concentrated. The product diethyl ((4-chlorophenyl) ((tetrahydrofuran-2-yl) oxy) methyl) phosphonate (compound 2) was obtained as a white solid (32.50 g, 93.2% yield) and was used in the next step without purification.
(2) Compound 2 (32.50 g,93.2 mmol) was dissolved in 250mL tetrahydrofuran under anhydrous and anaerobic conditions and cooled to-78 ℃. n-BuLi (120.0 mmol,2.5M in n-hexane) was slowly added dropwise to the above solution. The mixture was heated to-40℃and reacted for 1 to 2 hours, and a solution of cyclopropylmethyl ketone (12.2.+ -. 0.4g, 145.0.+ -. 5.0 mmol) in tetrahydrofuran (30 mL) was slowly dropped into the reaction mixture to continue the reaction for 1 hour. The mixture was slowly warmed to 0 ℃ and stirring was continued for 1 hour. TLC monitored complete conversion of the reaction starting material to enol product. Adding H to the mixture 2 O (100 mL) quenched the reaction. After separation, the aqueous phase was extracted with ethyl acetate and taken up in saturated Na 2 CO 3 Washing with aqueous solution. The tetrahydrofuran and ethyl acetate phases were combined, dried and concentrated to give crude compound 3.
(3) The crude compound 3 was dissolved in 150mL of a mixed solvent of tetrahydrofuran/water=1/1, and 36% hydrochloric acid solution (11 g,110 mmol) was slowly added dropwise to the reaction mixture, followed by stirring at room temperature for 0.5 to 1.5 hours. TLC monitored complete conversion of reaction compound 3 to compound 4. The mixture was separated, and the aqueous phase was extracted with ethyl acetate. Combining tetrahydrofuran and ethyl acetate solution, sequentially using saturated NaHCO 3 And saturated NaCl washing. The organic phase was concentrated by drying to give the crude product. The crude product was distilled under reduced pressure to give 1- (4-chlorophenyl) -2-cyclopropylpropane-1-one 4 (19.23 g, content 98.2%, yield 97.09%), 0.29mmhg, bp=75-85 ℃ C., product as colorless clear liquid. The overall yield of the reaction was 90.49%.
FIGS. 2 and 3 show nuclear magnetic resonance of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone 4 as the product in example 1 1 HNMR) detection results. From the diagrams and the spectrograms of FIG. 3It was found that the peak area was 4 between 7.82 and 7.84ppm, the peak area was 1 at 2.72ppm for four hydrogens of the benzene ring, the peak area was 3 between 1.24 and 1.25ppm for hydrogens on the CH, the peak area was 5 between 0.13 and 1.03ppm for 3 hydrogens on the methyl, and the peak area was 5 for 5 hydrogens of the three-membered ring. Characteristic peaks of 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone appear in the spectrograms, and the method proves that the method successfully synthesizes the 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone.
Example 21 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the solvent methylene chloride in step (1) was replaced with an equal amount of anhydrous toluene. A total of 18.75g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 98.3% in total yield 88.32%.
Example 3 1 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the solvent in step (1) was replaced with the same amount of anhydrous tetrahydrofuran. A total of 18.48g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 98.1% content and 86.87% overall yield.
Example 41 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the solvent in step (1) was replaced with the same amount of anhydrous dichloroethane. A total of 18.51g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 97.8% content and 86.74% overall yield.
Example 51 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the catalyst amount in step (1) was changed to 5mmol,1.26 g. A total of 18.76g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 97.5% content and a total yield of 87.65%.
Example 61 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the catalyst amount in step (1) was changed to 50mmol and 12.6 g. A total of 19.02g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 98.0% in total yield 89.32%.
Example 71 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the catalyst in step (1) was replaced with hydrogen fluoride pyridine (10 mmol,1.0 g). A total of 18.80g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 98.3% in total yield 88.55%.
Example 81 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the catalyst in step (1) was replaced with triethylamine hydrogen fluoride (10 mmol,1.6 g). A total of 18.64g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 97.8% content and a total yield of 87.35%.
Example 9 1 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the catalyst in step (1) was replaced with tetrabutylammonium tribromide and pyridinium p-toluenesulfonate (10 mmol,1:4,3.0 g). A total of 20.13g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 98.5% in total yield 95.01%.
Example 10 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the catalyst in step (1) was replaced with tetrabutylammonium tribromide and hydrogen fluoride pyridine (10 mmol,1:3,2.0 g). A total of 19.97g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 98.1% in total yield 93.87%.
Example 11 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the catalyst in step (1) was replaced with tetrabutylammonium tribromide and triethylamine hydrogen fluoride (10 mmol,1:2,2.7 g). A total of 19.81g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained in an amount of 97.6% and a total yield of 92.65%.
Example 12 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the tetrahydrofuran solvent in step (2) was replaced with toluene in the same amount. A total of 18.35g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 98.0% content and a total yield of 86.17%.
Example 13 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the solvent tetrahydrofuran in step (2) was replaced with an equivalent amount of methylene chloride. A total of 18.46g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 98.2% in 86.86% overall yield.
Example 14 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the tetrahydrofuran solvent in step (2) was replaced with the same amount of dichloroethane. A total of 18.61g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 98.1% content and a total yield of 87.48%.
Example 15 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the amount of the base used in the step (2) was changed to 101.2mmol and 6.5 g. A total of 18.52g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 97.9% in total yield 86.88%.
EXAMPLE 16 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the amount of the base used in the step (2) was changed to 185.2mmol and 11.9 g. A total of 18.29g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 97.6% content and 85.54% overall yield.
EXAMPLE 17 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the base in step (2) was replaced with lithium diisopropylamide (120.0 mmol,12.9 g). A total of 18.43g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 97.5% in total yield 86.10%.
Example 18 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the base in step (2) was replaced with sodium amide (120.0 mmol,4.7 g). A total of 18.35g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 98.3% in total yield 86.43%.
Example 19 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the base in step (2) was replaced with sodium t-butoxide (120.0 mmol,11.5 g). A total of 18.52g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 97.8% in total yield 86.79%.
Example 20 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the amount of cyclopropylmethyl ketone used in step (2) was changed to 103.0mmol and 8.7 g. A total of 18.71g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 97.6% in total yield 87.50%.
Example 21 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the amount of cyclopropylmethyl ketone used in step (2) was changed to 185.4.0mmol and 15.6 g. A total of 18.64g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 98.0% content and a total yield of 87.53%.
Example 22 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the acid in step (3) was replaced with acetic acid (110 mmol,6.6 g). A total of 18.50g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 97.8% in total yield 86.70%.
Example 23 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the acid in step (3) was replaced with p-toluenesulfonic acid (110 mmol,18.9 g). A total of 18.43g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 98.1% in total yield 86.63%.
EXAMPLE 24 preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Example 1 was repeated except that the acid in step (3) was replaced with sulfuric acid (55 mmol,5.4 g). A total of 18.86g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 98.0% content and a total yield of 88.57%.
Comparative example 11 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
1- (4-chlorophenyl) -2-cyclopropyl-1-propanone was prepared according to the method disclosed in patent document CN106883266a, in particular as follows
(1) Dimethyl α -hydroxy p-chlorobenzyl phosphonate 1 (2.51 g,10.0 mmol) was dissolved in toluene (50 mL) followed by 3, 4-2H-dihydropyran (841 mg,10.0 mmol) and p-toluene sulfonic acid (190 mg,1.0 mmol). The reaction solution was stirred at 50℃for 5 hours. After the completion of the reaction, the reaction solution was washed with sodium hydroxide solution (20 mL) and the separated layers were concentrated under reduced pressure to remove toluene. The crude product obtained was purified by column chromatography (petroleum ether: ethyl acetate=3:1) to give compound 2 (3.24 g), content 93.0%, yield 86.4%.
(2) A solution of diisopropylamine (0.51 g,5.0 mmol) in tetrahydrofuran (10.0 mL) was cooled to-78deg.C, then n-butyllithium (3.1 mL, 1.6M) was added dropwise to the solution, and the resulting solution was stirred at 0deg.C for 30 minutes and then cooled to-40deg.C. Then, compound 2 (1.95 g,5.0 mmol) and cyclopropylmethyl ketone (505 mg,6.0 mmol) were successively dropped into the reaction system, and the reaction solution was naturally warmed to 0℃and stirred at that temperature for 3 hours. After the reaction, the reaction mixture was cooled to 0℃and quenched by dropping a saturated ammonium chloride solution (10 mL). Extraction with ethyl acetate (three extractions of 15mL each). The resultant organic phases were combined, dried over sodium sulfate and concentrated to give crude compound 3 (1.55 g), content 85.0%, yield 89.99%.
(3) Compound 3 (1.45 g) obtained in step (2) was dissolved in tetrahydrofuran (5.0 mL), and then a 30% dilute sulfuric acid solution (1.0 mL) was added to the solution. The reaction solution was stirred at 25℃for 30 minutes. After the reaction was completed, the solvent was distilled off under reduced pressure. The crude product obtained was purified by column chromatography (petroleum ether: ethyl acetate=20:1) to give 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (0.96 g), a colorless oily compound, content 95.0%, yield 97.12%. The overall reaction yield was 75.51%.
Comparative example 21 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Comparative example 1 was conducted except that the p-toluenesulfonic acid in step (1) was replaced with the same amount of PPTS. A total of 0.97g of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (compound 4) was obtained, 95.5% in total, 78.36% in total reaction yield.
Comparative example 3 1 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
The procedure of comparative example 1 was followed except that the dihydropyran in step (1) was replaced with an equivalent amount of dihydrofuran, and the amount of compound 2 in step (2) was replaced with (1.87 g,5 mmol). 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (Compound 4) was obtained in a total amount of 1.02g, 95.5% and a total yield of 81.65%.
Comparative example 41 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Comparative example 1 was conducted except that the dihydropyran in step (1) was replaced with an equivalent amount of dihydrofuran, the p-toluenesulfonic acid in step (1) was replaced with an equivalent amount of PPTS, and the amount of compound 2 in step (2) was replaced with (1.87 g,5 mmol). 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (Compound 4) was obtained in a total amount of 1.01g, 96.0% and a total yield of 86.41%.
Comparative example 51 preparation of- (4-chlorophenyl) -2-cyclopropyl-1-propanone
Comparative example 1 was conducted in the same manner as in comparative example 1 except that the dihydropyran in step (1) was replaced with an equivalent amount of dihydrofuran, the p-toluenesulfonic acid in step (1) was replaced with an equivalent amount of tetrabutylammonium tribromide, PPTS1:1, and the amount of Compound 2 in step (2) was replaced with (1.87 g,5 mmol). 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone (Compound 4) was obtained in a total amount of 1.01g, 97.8% and a total yield of 88.82%.
TABLE 1 summary of the reaction conditions and three-step total yields for examples 1-24 and comparative examples 1-5
According to the test data of examples 1-6 and 12-24, it can be seen that dihydrofuran is used as a protecting group, PPTS is combined as a catalyst, the reaction yield is above 85%, and compared with examples 1,7 and 8, tetrabutylammonium tribromide is additionally added in examples 9-11, the reaction yield is significantly improved, especially when tetrabutylammonium tribromide is added: ppts=1:4, the reaction yield is up to 95%.
In comparative example 1, dihydropyran is used as a protecting group, p-toluenesulfonic acid is used as a catalyst, and the reaction yield is only 75.51%; in comparative example 2, the catalyst is replaced by PPTS, the reaction rate is slower, and the yield is improved slightly but still is still 80%; comparative example 3 the alternative protecting group was dihydrofuran, the catalyst was p-toluene sulfonic acid, and the reaction yield was likewise less than 82%. Comparative examples 4 and 5 the reaction yield was greatly improved to 85% or more by using the dihydrofuran protecting group of the present invention and a specific catalyst (catalyst composed of PPTS, tetrabutylammonium tribromide and PPTS).
Therefore, the reaction yield is closely related to the kind of the protecting group and the catalyst. Compared with dihydropyran, the dihydrofuran has higher selectivity to a reaction substrate, and the PPTS catalyst has weaker acidity, thereby being beneficial to reducing the influence on the reaction substrate and further improving the reaction yield, but simultaneously has the problem of low reaction rate, and the reaction rate and the yield can be improved by adding a small amount of tetrabutylammonium tribromide. The invention adopts the combination of the dihydrofuran protecting group and the specific catalyst to improve the reaction selectivity and the reaction yield.
Claims (11)
1. A process for the preparation of 1- (4-chlorophenyl) -2-cyclopropyl-1-propanone comprising:
(1) Reacting alpha-hydroxy p-chlorobenzyl phosphonate and 2, 3-dihydrofuran in the presence of a catalyst and a solvent to obtain diethyl ((4-chlorophenyl) ((tetrahydrofuran-2-yl) oxy) methyl) phosphonate; the catalyst consists of tetrabutylammonium tribromide and pyridinium p-toluenesulfonate, wherein the molar ratio of the tetrabutylammonium tribromide to the pyridinium p-toluenesulfonate is 1: (2-6); alternatively, the catalyst consists of tetrabutylammonium tribromide and hydrogen fluoride, wherein the molar ratio of tetrabutylammonium tribromide to hydrogen fluoride is 1: (2-6); alternatively, the catalyst consists of tetrabutylammonium tribromide and triethylamine hydrogen fluoride, and the molar ratio of tetrabutylammonium tribromide to triethylamine hydrogen fluoride is 1: (2-6);
(2) Diethyl ((4-chlorophenyl) ((tetrahydrofuran-2-yl) oxy) methyl) phosphonate and cyclopropylmethyl ketone are reacted in the presence of a base and a solvent to give compound 3;
(3) Carrying out hydrolysis reaction on the compound 3 under an acidic condition to obtain 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone;
2. the process according to claim 1, wherein the α -hydroxy p-chlorobenzyl phosphonate, 2, 3-dihydrofuran and catalyst in step (1) are fed in a molar ratio of 1:1.0 to 2.0:0.01 to 1.
3. The process according to claim 1, wherein the molar ratio of tetrabutylammonium tribromide to pyridinium p-toluenesulfonate is 1:4, a step of; the molar ratio of tetrabutylammonium tribromide to hydrogen fluoride pyridine is 1:3, a step of; the molar ratio of tetrabutylammonium tribromide to hydrogen fluoride triethylamine is 1:2.
4. the method of claim 1, wherein the reaction conditions of step (1) are: reacting for 1-8 hours at the temperature of 0-25 ℃.
5. The process according to claim 1, wherein the reaction in step (1) is completed further comprising the following post-treatment steps: the reaction solution after the reaction is finished is saturated NaHCO 3 And saturated NaCl solution, and drying and concentrating the organic phase to obtain diethyl ((4-chlorophenyl) ((tetrahydrofuran-2-yl) oxy) methyl) phosphonate.
6. The process according to claim 1, wherein the diethyl ((4-chlorophenyl) ((tetrahydrofuran-2-yl) oxy) methyl) phosphonate, cyclopropylmethyl ketone and base are fed in a molar ratio of 1:1.0 to 2.0:1.0 to 2.0; wherein the alkali comprises, but is not limited to, any one or more of lithium diisopropylamide, n-butyllithium, sodium amide or sodium tert-butoxide, and the mixture is obtained by combining the above materials according to any proportion; the reaction conditions are as follows: reacting for 1-10 hours at the temperature of minus 78-0 ℃.
7. The method according to claim 6, wherein the reaction conditions are: adding alkali and cyclopropyl methyl ketone at the temperature of minus 78 ℃ to 0 ℃, and reacting for 2 to 8 hours at the temperature of minus 40 ℃ to 0 ℃ after the addition is finished.
8. The process according to claim 1, wherein the reaction in step (2) is completed by further performing the following post-treatment steps: after the reaction, adding water for quenching, and concentrating to obtain the compound 3.
9. The process according to claim 1, wherein the compound 3 and the acid are fed in a molar ratio of 1:1.0 to 2.0.
10. The preparation method according to claim 1, wherein the hydrolysis reaction in the step (3) is to dissolve the compound 3 in a solvent, add a catalyst, add an acid dropwise, and hydrolyze the compound in an acidic condition of 0-60 ℃ for 0.5-1.2 hours after the completion of the addition; wherein the acid includes, but is not limited to, any one or more of acetic acid, hydrochloric acid, p-toluenesulfonic acid or sulfuric acid;
the step (3) further comprises a post-treatment step after the reaction is finished: after the reaction is finished, the reaction solution is concentrated, separated and purified to obtain the 1- (4-chlorophenyl) -2-cyclopropyl-1-acetone.
11. The process according to claim 1, wherein the solvent includes, but is not limited to, any one or any combination of more than one of dichloromethane, toluene, tetrahydrofuran, or 1, 2-dichloroethane.
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