CN112358462A - Synthetic method of piperonyl derivatives - Google Patents
Synthetic method of piperonyl derivatives Download PDFInfo
- Publication number
- CN112358462A CN112358462A CN202011249863.4A CN202011249863A CN112358462A CN 112358462 A CN112358462 A CN 112358462A CN 202011249863 A CN202011249863 A CN 202011249863A CN 112358462 A CN112358462 A CN 112358462A
- Authority
- CN
- China
- Prior art keywords
- room temperature
- reaction
- formula
- organic solvent
- dichloromethane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 title claims abstract description 14
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 14
- 238000001308 synthesis method Methods 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 238000001914 filtration Methods 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- 239000012629 purifying agent Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003208 petroleum Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 238000012805 post-processing Methods 0.000 claims description 4
- 238000004537 pulping Methods 0.000 claims description 4
- 230000000171 quenching effect Effects 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 238000000643 oven drying Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 238000005917 acylation reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 229960005235 piperonyl butoxide Drugs 0.000 description 8
- HEJLFBLJYFSKCE-UHFFFAOYSA-N 2',3'-Dihydroxyacetophenone Chemical compound CC(=O)C1=CC=CC(O)=C1O HEJLFBLJYFSKCE-UHFFFAOYSA-N 0.000 description 6
- -1 [1,3] dioxol-4-yl Chemical group 0.000 description 5
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- GZTMCZAOQTVOJK-UHFFFAOYSA-N 1,3-dioxolan-4-one Chemical compound O=C1COCO1 GZTMCZAOQTVOJK-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- SQDPLHUWINEGDN-UHFFFAOYSA-N 2-(1,3-dioxol-4-yl)acetaldehyde Chemical compound O=CCC1=COCO1 SQDPLHUWINEGDN-UHFFFAOYSA-N 0.000 description 2
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- 235000002566 Capsicum Nutrition 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 206010048723 Multiple-drug resistance Diseases 0.000 description 1
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000006002 Pepper Substances 0.000 description 1
- 235000016761 Piper aduncum Nutrition 0.000 description 1
- 235000017804 Piper guineense Nutrition 0.000 description 1
- 244000203593 Piper nigrum Species 0.000 description 1
- 235000008184 Piper nigrum Nutrition 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940093265 berberine Drugs 0.000 description 1
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 description 1
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003175 pesticide synergist Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate 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
- 235000013599 spices Nutrition 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthesis method of a piperonyl ring derivative, which prepares a 7-bromobenzo [ D ] [1,3] dioxol-4-one piperonyl ring derivative through acylation reaction, substitution reaction and reaction with dihalomethane. The method has the advantages of high yield, high purity, short synthesis steps, conventional and easily-obtained starting materials, low cost and environmental friendliness, and has good industrial application prospect.
Description
Technical Field
The invention belongs to the technical field of synthesis, and particularly relates to a synthesis method of a piperonyl cycloderivative.
Background
The chemical name of the piperonyl is 1, 3-benzodioxole, the piperonyl butoxide is an important intermediate for synthesizing pesticide synergist piperonyl butoxide and berberine as medicine, and a series of fine chemicals with high added value can be derived by introducing various groups on benzene ring and methylene, and the piperonyl can be widely applied to the fields of spices, pesticides, medicines and the like.
The pepper ring structure unit is closely related to the anti-tumor activity, the derivative thereof has good cytotoxic activity to human colon cancer cells and nasopharyngeal carcinoma cells with multiple drug resistance, and the in-vivo drug effect of the derivative also shows excellent tumor inhibition activity. The 7-bromobenzo [ D ] [1,3] dioxol-4-one substance belongs to piperonyl derivatives and is a key intermediate for drug synthesis. However, the price of the currently marketed 7-bromobenzo [ D ] [1,3] dioxol-4-one is high, for example, the price of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one (CAS: 1892297-18-6) marketed reaches hundreds of dollars per gram, and the purity only reaches 95% -98%, which hinders the further application of the compound as a pharmaceutical intermediate.
Therefore, the synthesis method of the-bromobenzo [ D ] [1,3] dioxol-4-one piperonylenecarbon derivatives, which has the advantages of high yield, high purity, short synthesis steps, conventional and easily-obtained starting materials, low cost, environmental friendliness and industrial production prospect, is of great significance.
Disclosure of Invention
The invention provides a synthesis method of a piperonyl cycloderivative, which comprises the following steps:
(1) carrying out substitution reaction on the compound shown in the formula I and bromine under the action of alkali to obtain a compound shown in a formula II;
(2) reacting the compound shown in the formula II obtained in the step (1) with dihalomethane under the action of inorganic base to obtain a piperonyl-cyclo derivative shown in the formula III;
the reaction route is as follows:
wherein R is C1～5Alkyl, preferably R is methyl.
Further, the base in the step (1) is selected from tert-butylamine, diisopropylethylamine, triethylamine, N-methylmorpholine, triethylenediamine or tetramethylethylenediamine; or, the inorganic base in the step (2) is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide, and the dihalomethane is selected from dichloromethane, dibromomethane or diiodomethane.
Further, the molar ratio of the compound shown in the formula I in the step (1) to the bromine and the alkali is 1 (1-2) to 2-5; the reaction conditions are as follows: reacting for 1-3 hours at-10 to-50 ℃ in an organic solvent; preferably, the organic solvent is selected from toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane.
Further, the step (1) further comprises the following post-processing steps: heating to room temperature, filtering to obtain a filter cake, adding a purifying agent A, heating for refluxing, cooling to room temperature, stirring, filtering to obtain a filter cake, washing with the purifying agent A again, and drying; the purifying agent A is selected from petroleum ether, n-hexane, toluene and dichloromethane, and is preferably petroleum ether.
Further, the molar ratio of the compound shown in the formula II in the step (2) to the dihalomethane and the inorganic base is 1 (1-2) to 2-5; the reaction conditions are as follows: reacting in an organic solvent at 70-160 ℃ for 4-5 hours; preferably, the organic solvent is selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, dioxane, acetonitrile.
Further, the step (2) further comprises the following post-processing steps: cooling to room temperature, adjusting pH to acidity, extracting, drying, concentrating, adding a purifying agent B, heating and refluxing, cooling to room temperature, stirring, filtering to obtain a filter cake, and drying; the purifying agent B is selected from n-heptane, n-hexane, petroleum ether, toluene and dichloromethane, and is preferably n-heptane.
Further, the compound shown in the formula I is obtained by reacting catechol with an acylating agent under the action of Lewis acid.
Furthermore, the molar ratio of the catechol to the acylating agent to the Lewis acid is 1 (1-2) to 2-5, and the reaction conditions are as follows: reacting in an organic solvent or without adding a solvent, wherein the reaction temperature range is as follows: the reaction time is 3-4 hours from room temperature to the reflux temperature of the organic solvent; preferably, the organic solvent is selected from dichloromethane, dichloroethane, nitromethane, nitrobenzene, carbon disulfide. Still further, the following post-processing steps are included: quenching reaction at room temperature, extracting, separating, collecting organic phase, concentrating, adding purifying agent C, stirring at room temperature, pulping, filtering, and oven drying filter cake; the purifying agent C is selected from n-heptane, n-hexane, petroleum ether, toluene and dichloromethane, and is preferably n-heptane. The method of quenching the reaction is preferably by adding water or hydrochloric acid.
Experimental results show that the synthesis method for preparing the piperonyl cycloderivatives has the advantages of high yield, high purity, short synthesis steps, conventional and easily-obtained starting materials, low cost and environmental friendliness, and has good application prospects.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The starting materials used in the present invention are all known products, obtained by purchasing commercially available products.
Example 1 Synthesis of 2, 3-dihydroxy acetophenone (Compound of formula I)
Adding zinc dichloride (34.1g, 0.25mol) and acetic acid (9.0g, 0.15mol) into a reaction bottle, heating to 80 ℃, stirring to dissolve, adding catechol (11g, 0.1mol), heating to 100 ℃, and reacting for 4 hours. Cooling to room temperature, adding water (200ml) to quench the reaction, extracting with ethyl acetate (100ml × 3 times), mixing the organic phases, concentrating to dryness to obtain a crude product, adding n-heptane (100ml), stirring and pulping at room temperature for 1h, filtering, and drying the filter cake to obtain 12.2g of 2, 3-dihydroxy acetophenone, with a yield of 80.3% and a purity of 98.8%.
Example 2 Synthesis of 2, 3-dihydroxy acetophenone (Compound of formula I)
Aluminum trichloride (33.34g, 0.25mol), acetyl chloride (9.42g, 0.12mol) and methylene chloride (550ml) were added to a reaction flask, stirred for 30 minutes, and then catechol (11g, 0.1mol) was added, and reacted at room temperature for 3 hours after the addition. The reaction was quenched by the addition of 2N hydrochloric acid (200ml), the layers were separated, and the organic phase was washed with tap water (150 ml. times.2) and dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate to obtain crude product, adding n-heptane (100ml), stirring and pulping at room temperature for 1h, filtering, and oven drying the filter cake to obtain 12.7g of 2, 3-dihydroxy acetophenone with yield of 83.6% and purity of 98.6%.
Example 3 Synthesis of 2, 3-dihydroxy-4-bromoacetophenone (Compound of formula II)
Adding tert-butylamine (28.5g, 0.39mol) and toluene (100ml) into a reaction bottle, cooling to-10-15 ℃, dropwise adding bromine (33.6g, 0.21mol), continuously cooling to-30-40 ℃ after dropwise adding, dropwise adding a toluene (100ml) solution of 2, 3-dihydroxyacetophenone (20g, 0.13mol), and keeping the temperature of-30-40 ℃ for reaction for 2 hours after dropwise adding. Heating to room temperature, and filtering to obtain a crude product. Adding 250ml of petroleum ether, heating and refluxing for 1h, cooling to room temperature, stirring for 2h, filtering, washing a filter cake by using a small amount of petroleum ether, and drying to obtain 26.5g of 2, 3-dihydroxy-4-bromoacetophenone with the yield of 87.2%. The purity is 98.3%.
Example 4 Synthesis of 2, 3-dihydroxy-4-bromoacetophenone (Compound of formula II)
Adding diisopropylethylamine (50.4g, 0.39mol) and toluene (100ml) into a reaction bottle, cooling to-10-15 ℃, dropwise adding bromine (33.6g, 0.21mol), continuously cooling to-30-40 ℃ after dropwise adding, dropwise adding a toluene (100ml) solution of 2, 3-dihydroxyacetophenone (20g, 0.13mol), and reacting for 2.5h at-30-40 ℃. Heating to room temperature, and filtering to obtain a crude product. Adding 250ml of petroleum ether, heating and refluxing for 1h, cooling to room temperature, stirring for 2h, filtering, washing a filter cake by using a small amount of petroleum ether, and drying to obtain 24.7g of 2, 3-dihydroxy-4-bromoacetophenone with the yield of 81.3%. The purity is 98.2%.
EXAMPLE 5 Synthesis of the Piperazinocycle derivative 1- (7-bromobenzo [ d ] [1,3] dioxol-4-yl) ethan-1-one (Compound of formula III)
Potassium carbonate (44.7g, 0.324mol), N-dimethylformamide (200ml) and dibromomethane (24.3g, 0.14mol) were added to a reaction flask, and a solution of 2, 3-dihydroxy-4-bromoacetophenone (25g, 0.108mol) in N, N-dimethylformamide (50ml) was slowly added dropwise thereto, after which the temperature was raised to an internal temperature of 100 ℃ for reaction for 5 hours. Cooled to room temperature, adjusted to pH 4 with 2N hydrochloric acid, extracted with ethyl acetate (100 ml. times.3), dried over anhydrous sodium sulfate and concentrated in the dry crude. Adding 200ml of n-heptane, heating and refluxing for 1h, cooling to room temperature, stirring for 2h, filtering, and drying to obtain 21.2g of piperonyl derivative 7-bromobenzo [ D ] [1,3] dioxol-4-ethanone, wherein the yield of the step is 80.7%, and the purity is 99.3%.
The experimental results are as follows:1H-NMR(400MHz,DMSO-d6):δ7.21(d,1H),7.16(d,1H),6.29(s,2H),2.51(s,3H)。
LCMS:m/z 244.1(M+H+)。
EXAMPLE 6 Synthesis of the Piperazino derivative 1- (7-bromobenzo [ d ] [1,3] dioxol-4-yl) ethan-1-one (Compound of formula III)
Sodium hydroxide (10.8g, 0.27mol), N-methylpyrrolidone (200ml) and dibromomethane (24.3g, 0.14mol) were added to a reaction flask, and a solution of 2, 3-dihydroxy-4-bromoacetophenone (25g, 0.108mol) in N-methylpyrrolidone (50ml) was slowly added dropwise thereto, after which the temperature was raised to an internal temperature of 120 ℃ for reaction for 4 hours. Cooled to room temperature, adjusted to pH 4 with 2N hydrochloric acid, extracted with ethyl acetate (100 ml. times.3), dried over anhydrous sodium sulfate and concentrated in the dry crude. Adding 200ml of n-heptane, heating and refluxing for 1h, cooling to room temperature, stirring for 2h, filtering, and drying to obtain 20.8g of piperonyl derivative 7-bromobenzo [ D ] [1,3] dioxol-4-ethanone, wherein the yield of the step is 79.2%. The purity is 99.1%.
The experimental results are as follows:1H-NMR(400MHz,DMSO-d6):δ7.21(d,1H),7.16(d,1H),6.29(s,2H),2.51(s,3H)。
LCMS:m/z 244.1(M+H+)。
according to the calculation of the result, the total yield of the synthesized product piperonyl derivative 1- (7-bromobenzo [ d ] [1,3] dioxol-4-yl) ethan-1-one can reach 51.7% -58.8%, and the purity of the final product is higher than 99%.
In conclusion, the synthesis method of the piperonyl cycloderivatives provided by the invention has the advantages of high yield, high purity, short synthesis steps, conventional and easily available starting materials, low cost and environmental friendliness, and has a good industrial application prospect.
Claims (10)
1. A synthesis method of piperonyl derivatives is characterized by comprising the following steps:
(1) carrying out substitution reaction on the compound shown in the formula I and bromine under the action of alkali to obtain a compound shown in a formula II;
(2) reacting the compound shown in the formula II obtained in the step (1) with dihalomethane under the action of inorganic base to obtain a piperonyl-cyclo derivative shown in the formula III;
the reaction route is as follows:
wherein R is C1～5Alkyl, preferably R is methyl.
2. The method of claim 1, wherein the base of step (1) is selected from tert-butylamine, diisopropylethylamine, triethylamine, N-methylmorpholine, triethylenediamine, or tetramethylethylenediamine; or, the inorganic base in the step (2) is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide, and the dihalomethane is selected from dichloromethane, dibromomethane or diiodomethane.
3. The synthesis method of claim 1, wherein the molar ratio of the compound represented by formula I in step (1) to the bromine and the base is 1 (1-2) to (2-5); the reaction conditions are as follows: reacting for 1-3 hours at-10 to-50 ℃ in an organic solvent; preferably, the organic solvent is selected from toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane.
4. The synthesis method according to claim 3, wherein the step (1) further comprises the following post-treatment steps: heating to room temperature, filtering to obtain a filter cake, adding a purifying agent A, heating for refluxing, cooling to room temperature, stirring, filtering to obtain a filter cake, washing with the purifying agent A again, and drying; the purifying agent A is selected from petroleum ether, n-hexane, toluene and dichloromethane, and is preferably petroleum ether.
5. The synthesis method of claim 1, wherein the molar ratio of the compound of formula II in the step (2) to the dihalomethane and the inorganic base is 1 (1-2) to (2-5); the reaction conditions are as follows: reacting in an organic solvent at 70-160 ℃ for 4-5 hours; preferably, the organic solvent is selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, dioxane, acetonitrile.
6. The synthesis method according to claim 5, wherein the step (2) further comprises the following post-treatment steps: cooling to room temperature, adjusting pH to acidity, extracting, drying, concentrating, adding a purifying agent B, heating and refluxing, cooling to room temperature, stirring, filtering to obtain a filter cake, and drying; the purifying agent B is selected from n-heptane, n-hexane, petroleum ether, toluene and dichloromethane, and is preferably n-heptane.
7. The process of claim 1, wherein the compound of formula I is obtained by reacting catechol with an acylating agent under the action of a lewis acid.
8. The synthesis method of claim 7, wherein the molar ratio of catechol to the acylating agent and the Lewis acid is 1 (1-2) to (2-5), and the reaction conditions are as follows: reacting in an organic solvent or without adding a solvent, wherein the reaction temperature range is as follows: the reaction time is 3-4 hours from room temperature to the reflux temperature of the organic solvent; preferably, the organic solvent is selected from dichloromethane, dichloroethane, nitromethane, nitrobenzene, carbon disulfide.
9. The method of synthesis of claim 8, further comprising the post-processing steps of: quenching reaction at room temperature, extracting, separating, collecting organic phase, concentrating, adding purifying agent C, stirring at room temperature, pulping, filtering, and oven drying filter cake; the purifying agent C is selected from n-heptane, n-hexane, petroleum ether, toluene and dichloromethane, and is preferably n-heptane.
10. The method of synthesis of claim 9, wherein the quenching reaction is carried out by adding water or hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011249863.4A CN112358462B (en) | 2020-11-10 | 2020-11-10 | Synthesis method of piper-nigrum ring derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011249863.4A CN112358462B (en) | 2020-11-10 | 2020-11-10 | Synthesis method of piper-nigrum ring derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112358462A true CN112358462A (en) | 2021-02-12 |
| CN112358462B CN112358462B (en) | 2023-11-10 |
Family
ID=74509685
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011249863.4A Active CN112358462B (en) | 2020-11-10 | 2020-11-10 | Synthesis method of piper-nigrum ring derivative |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112358462B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113480512A (en) * | 2021-07-23 | 2021-10-08 | 阜阳欣奕华制药科技有限公司 | Preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone |
| CN113603670A (en) * | 2021-07-23 | 2021-11-05 | 阜阳欣奕华制药科技有限公司 | Method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one |
| CN114773309A (en) * | 2022-04-12 | 2022-07-22 | 乐威医药(天津)有限公司 | Preparation method and application of 1- (7-halobenzo [ D ] [1,3] dioxol-4-yl) alkyl ketone compound |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617543A (en) * | 2012-03-13 | 2012-08-01 | 天津科技大学 | Synthesis methods for piperonyl ethanol and derivatives thereof |
| CN103347859A (en) * | 2010-07-15 | 2013-10-09 | 台睿生物科技股份有限公司 | Synthesis and anticancer activity of aryl and heteroaryl-quinolin derivatives |
| CN108675998A (en) * | 2018-06-28 | 2018-10-19 | 北京凯因科技股份有限公司 | A kind of crystallinity methyl carbamate class compound |
| CN111807933A (en) * | 2020-07-21 | 2020-10-23 | 江西博雅欣和制药有限公司 | Novel preparation method of medical intermediate 3-bromocatechol |
-
2020
- 2020-11-10 CN CN202011249863.4A patent/CN112358462B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103347859A (en) * | 2010-07-15 | 2013-10-09 | 台睿生物科技股份有限公司 | Synthesis and anticancer activity of aryl and heteroaryl-quinolin derivatives |
| CN102617543A (en) * | 2012-03-13 | 2012-08-01 | 天津科技大学 | Synthesis methods for piperonyl ethanol and derivatives thereof |
| CN108675998A (en) * | 2018-06-28 | 2018-10-19 | 北京凯因科技股份有限公司 | A kind of crystallinity methyl carbamate class compound |
| CN111807933A (en) * | 2020-07-21 | 2020-10-23 | 江西博雅欣和制药有限公司 | Novel preparation method of medical intermediate 3-bromocatechol |
Non-Patent Citations (3)
| Title |
|---|
| LINGHUA CAO等: "SYNTHESIS OF 3-(3-ALKYL-5-THIOXO-1H-4,5-DIHYDRO-1,2,4-TRIAZOL-4-YL)- AMINOCARBONYLCHROMONES", 《CHEMISTRY OF HETEROCYCLIC COMPOUNDS》 * |
| MOHSEN MORADIAN等: "Zncl2@MWCNTs nanocomposite as an efficient and reusable catalyst for direct regioselective ortho C-acylation of phenolic compounds under solvent free and microwave conditions", 《GREEN CHEMISTRY LETTERS AND REVIEWS》 * |
| XUAN JU等: "Synthetic Studies toward Bazzanin K: Regioselective and Chemoselective Three-Component Suzuki Coupling", 《J. ORG. CHEM.》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113480512A (en) * | 2021-07-23 | 2021-10-08 | 阜阳欣奕华制药科技有限公司 | Preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone |
| CN113603670A (en) * | 2021-07-23 | 2021-11-05 | 阜阳欣奕华制药科技有限公司 | Method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one |
| CN113480512B (en) * | 2021-07-23 | 2022-07-29 | 阜阳欣奕华制药科技有限公司 | Preparation method of 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-ketone |
| CN113603670B (en) * | 2021-07-23 | 2022-07-29 | 阜阳欣奕华制药科技有限公司 | Method for preparing 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethyl-1-one |
| CN114773309A (en) * | 2022-04-12 | 2022-07-22 | 乐威医药(天津)有限公司 | Preparation method and application of 1- (7-halobenzo [ D ] [1,3] dioxol-4-yl) alkyl ketone compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112358462B (en) | 2023-11-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112358462A (en) | Synthetic method of piperonyl derivatives | |
| CN111718228A (en) | Method for synthesizing carboxylic acid for prolonging two carbon chains by olefin in one step | |
| CN110092760B (en) | 3-fluoroalkoxy-2 (1H) -quinoxalinone and synthetic method thereof | |
| CN114524795A (en) | Improved preparation method of Rhodomyrtone | |
| CN114315823A (en) | Intermediate of berberine hydrochloride and analogue thereof and preparation method thereof | |
| CN112778317B (en) | Synthetic method of [1,2,4] triazolo [1,5-a ] pyrimidine compound | |
| CN111675660B (en) | Preparation method for synthesizing palbociclib intermediate and method for synthesizing palbociclib | |
| CN110256451B (en) | Synthetic method of benzofuro [2,3-b ] quinoline derivative | |
| CN113336703A (en) | Synthesis of 1,3,4, 5-tetrasubstituted 1H-pyrazole derivatives | |
| CN112374973B (en) | Synthesis method of drug intermediate 4-bromo-2, 3-dihydroxybenzaldehyde | |
| CN110698422A (en) | Synthetic method of aromatic mercapto-diazole derivative | |
| CN109678862A (en) | A kind of preparation method of polysubstituted diphenylethyllene indole derivatives | |
| Shaabani et al. | Three-component, one-pot synthesis of 3, 4-dihydropyrimidin-2-(1 H)-ones catalyzed by bromodimethylsulfonium bromide | |
| AU781221B2 (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
| CN113683496B (en) | Synthetic method of agrimophol B and intermediate pseudo-secoisolariciresinol thereof | |
| CN110156681B (en) | Synthesis method of 2-ester group quinoline | |
| CN113372279B (en) | Synthetic method of 4, 5-dicyanoimidazole derivative | |
| Ikeda et al. | Carbazoledioxazines having long alkyl groups 1. Synthesis of carbazoledioxazines with linear type structure | |
| Brahmbhatt et al. | Synthesis of some 3-phenyl-4-methyl-6-(6-arylpyridin-2-yl)-and 3-phenyl-4-methyl-6-(4, 6-diarylpyridin-2-yl) coumarins | |
| Popandova-Yambolieva | Synthesis of new spiropyrrolidines and michael addition products using phase transfer catalyzed addition of schiff bases to 9-arylmethylenefluorenes | |
| CN117229181A (en) | Preparation method of methylsulfonylamino chalcone derivative | |
| CN117180248A (en) | Application of methylsulfonylamino chalcone derivative | |
| US3784547A (en) | Selected 5-substituted-5-phenylalkyl barbituric acids | |
| CN116768812A (en) | Synthesis method of polysubstituted 2, 5-dihydro-oxazole compound | |
| Marchalín et al. | Synthesis of cyano derivatives with diazaquaterphenyl skeleton |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |