CN112358462B - Synthesis method of piper-nigrum ring derivative - Google Patents
Synthesis method of piper-nigrum ring derivative Download PDFInfo
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 10
- 244000203593 Piper nigrum Species 0.000 title claims description 5
- 235000008184 Piper nigrum Nutrition 0.000 title claims description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 8
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000001914 filtration Methods 0.000 claims description 15
- 239000012629 purifying agent Substances 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 14
- 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
- 238000003756 stirring 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
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000003208 petroleum Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 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
- 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
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 5
- 238000000643 oven drying Methods 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 230000000171 quenching effect Effects 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 group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003513 alkali Substances 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
- 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
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical group 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
- 239000002585 base Substances 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
- 239000007788 liquid Substances 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
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 12
- 238000003786 synthesis reaction Methods 0.000 abstract description 12
- 230000007613 environmental effect Effects 0.000 abstract description 4
- 239000007858 starting material Substances 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
- HEJLFBLJYFSKCE-UHFFFAOYSA-N 2',3'-Dihydroxyacetophenone Chemical compound CC(=O)C1=CC=CC(O)=C1O HEJLFBLJYFSKCE-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- -1 [1,3] dioxol-4-yl Chemical group 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000722363 Piper Species 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
- 229960005235 piperonyl butoxide Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- GZTMCZAOQTVOJK-UHFFFAOYSA-N 1,3-dioxolan-4-one Chemical compound O=C1COCO1 GZTMCZAOQTVOJK-UHFFFAOYSA-N 0.000 description 2
- 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
- 229940093265 berberine Drugs 0.000 description 2
- 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 2
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 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
- 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 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- 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
- 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
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000004075 alteration Effects 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
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 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
- 239000000203 mixture Substances 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
- 239000002304 perfume Substances 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
- 239000002994 raw material Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 125000003944 tolyl group Chemical group 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthesis method of piperonyl derivatives, which prepares 7-bromobenzo [ D ] [1,3] dioxol-4-ketone piperonyl derivatives 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 available 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 piper-nigrum ring derivative.
Background
The piperonyl chemical name is 1, 3-benzodioxyzole, which is an important intermediate for synthesizing pesticide synergist piperonyl butoxide and berberine, and a series of fine chemicals with high added value can be derived by introducing various groups on benzene rings and methylene, so that the piperonyl butoxide and berberine can be widely applied to the fields of perfume, pesticide, medicine and the like.
The piper ring structural unit is closely related to the anti-tumor activity, and the derivatives of the piper ring structural unit have good cytotoxic activity on human colon cancer cells and nasopharyngeal carcinoma cells with multiple drug resistance, and the in vivo drug effect of the piper ring structural unit also shows excellent tumor inhibition activity. 7-bromobenzo [ D ] [1,3] dioxol-4-one substances belong to piperonyl derivatives and are key intermediates for drug synthesis. However, 7-bromobenzo [ D ] [1,3] dioxol-4-ones currently commercially available are expensive, such as 1- (7-bromobenzo [ D ] [1,3] dioxol-4-yl) ethan-1-one (CAS: 1892297-18-6), which has a commercial price of hundreds of meropenia-grams and a purity of only 95% -98%, and prevent further application thereof as pharmaceutical intermediates.
Therefore, the synthesis method of the-bromo-benzo [ D ] [1,3] dioxol-4-one piperonyl derivatives has the advantages of high yield, high purity, short synthesis steps, conventional and easily available starting materials, low cost, environmental friendliness and industrial production prospect, and has important significance.
Disclosure of Invention
The invention provides a synthesis method of piper-nigrum derivatives, which comprises the following steps:
(1) The compound shown in the formula I and bromine undergo substitution reaction under the action of alkali to obtain a compound shown in the 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 derivative shown in the formula III;
the reaction route is as follows:
wherein R is C 1～5 Alkyl, preferably R is methyl.
Further, 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 methylene dichloride, dibromomethane or diiodomethane.
Further, the mol ratio of the compound shown in the formula I in the step (1) to bromine to alkali is 1 (1-2) (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, methylene chloride, chloroform, carbon tetrachloride, dichloroethane.
Further, the step (1) further includes the following post-processing steps: heating to room temperature, filtering to obtain a filter cake, adding the purifying agent A, heating and 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 methylene dichloride, 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) (2-5); the reaction conditions are as follows: reacting in organic solvent at 70-160 deg.c for 4-5 hr; 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 includes the following post-processing steps: cooling to room temperature, regulating pH to acidity, extracting, drying, concentrating, adding purifying agent B, heating and refluxing, cooling to room temperature, stirring, filtering to obtain filter cake, and oven drying; the purifying agent B is selected from n-heptane, n-hexane, petroleum ether, toluene, dichloromethane, 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.
Further, the molar ratio of catechol to acylating agent and Lewis acid is 1 (1-2): 2-5, and the reaction conditions are: the reaction is carried out in an organic solvent or without adding solvent, and the reaction temperature ranges are 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 disulphide. Still further, the method further comprises the following post-processing steps: quenching reaction at room temperature, extracting, separating liquid, 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, dichloromethane, preferably n-heptane. The quenching reaction is preferably carried out by adding water or hydrochloric acid.
Experimental results show that the synthesis method for preparing the piper-ring derivative has the advantages of high yield, high purity, short synthesis steps, conventional and easily available starting materials, low cost and environmental friendliness, and has good application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The raw materials used in the invention are all known products and are obtained by purchasing commercial products.
EXAMPLE 1 Synthesis of 2, 3-dihydroxyacetophenone (Compound of formula I)
Zinc dichloride (34.1 g,0.25 mol) and acetic acid (9.0 g,0.15 mol) were added to the flask, heated to 80℃and dissolved with stirring, catechol (11 g,0.1 mol) was added, and then heated to 100℃to react for 4 hours. Cooling to room temperature, adding water (200 ml), quenching, extracting with ethyl acetate (100 ml×3 times), mixing organic phases, concentrating, drying to obtain crude product, adding n-heptane (100 ml), stirring at room temperature, pulping for 1 hr, filtering, and oven drying filter cake to obtain 2, 3-dihydroxyacetophenone 12.2g, yield 80.3%, purity 98.8%.
EXAMPLE 2 Synthesis of 2, 3-dihydroxyacetophenone (Compound of formula I)
Aluminum trichloride (33.34 g,0.25 mol), acetyl chloride (9.42 g,0.12 mol) and methylene chloride (550 ml) were added to the reaction flask, stirred for 30 minutes, then catechol (11 g,0.1 mol) was added, and after the addition was completed, the reaction was carried out at room temperature for 3 hours. The reaction was quenched by the addition of 2N hydrochloric acid (200 ml), the solution was 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 a crude product, adding n-heptane (100 ml), stirring and pulping for 1h at room temperature, filtering, and drying a filter cake to obtain 12.7g of 2, 3-dihydroxyacetophenone, wherein the yield is 83.6%, and the purity is 98.6%.
EXAMPLE 3 Synthesis of 2, 3-dihydroxy-4-bromoacetophenone (Compound of formula II)
Tert-butylamine (28.5 g,0.39 mol) and toluene (100 ml) are added into a reaction bottle, cooled to-10 to-15 ℃, bromine (33.6 g,0.21 mol) is added dropwise, cooled to-30 to-40 ℃ continuously after the dropwise addition, toluene (100 ml) solution of 2, 3-dihydroxyacetophenone (20 g,0.13 mol) is added dropwise, and the reaction is carried out for 2 hours at-30 to-40 ℃ after the dropwise addition. Heating to room temperature, and filtering to obtain crude product. 250ml petroleum ether is added, heating reflux is carried out for 1h, cooling to room temperature and stirring is carried out for 2h, filtering is carried out, filter cakes are washed by a small amount of petroleum ether, 26.5g of 2, 3-dihydroxyl-4-bromoacetophenone is obtained after drying, and the yield is 87.2%. The purity was 98.3%.
EXAMPLE 4 Synthesis of 2, 3-dihydroxy-4-bromoacetophenone (Compound of formula II)
Diisopropylethylamine (50.4 g,0.39 mol) and toluene (100 ml) were added to a reaction flask, cooled to-10 to-15 ℃, bromine (33.6 g,0.21 mol) was added dropwise, cooled to-30 to-40 ℃ continuously after the dropwise addition, toluene (100 ml) solution of 2, 3-dihydroxyacetophenone (20 g,0.13 mol) was added dropwise, and the reaction was carried out for 2.5 hours at-30 to-40 ℃ after the dropwise addition. Heating to room temperature, and filtering to obtain crude product. 250ml petroleum ether is added, heating reflux is carried out for 1h, cooling to room temperature and stirring is carried out for 2h, filtering is carried out, filter cakes are washed by a small amount of petroleum ether, 24.7g of 2, 3-dihydroxyl-4-bromoacetophenone is obtained after drying, and the yield is 81.3%. The purity was 98.2%.
EXAMPLE 5 Synthesis of piperonyl derivative 1- (7-bromobenzo [ d ] [1,3] dioxol-4-yl) ethan-1-one (Compound of formula III)
Potassium carbonate (44.7 g,0.324 mol), N-dimethylformamide (200 ml) and dibromomethane (24.3 g,0.14 mol) were added to the reaction flask, and then a solution of 2, 3-dihydroxy-4-bromoacetophenone (25 g,0.108 mol) in N, N-dimethylformamide (50 ml) was slowly added dropwise thereto, and after completion of the dropwise addition, the temperature was raised to an internal temperature of 100℃for reaction for 5 hours. Cooled to room temperature, the pH was adjusted to about 4 with 2N hydrochloric acid, extracted with ethyl acetate (100 ml. Times.3), dried over anhydrous sodium sulfate, and the dried crude product was concentrated. 200ml of n-heptane was added, heated and refluxed for 1 hour, cooled to room temperature and stirred for 2 hours, filtered and dried to obtain 21.2g of piperonyl derivative 7-bromobenzo [ D ] [1,3] dioxol-4-ethanone, the yield of this step being 80.7% and the purity being 99.3%.
Experimental results: 1 H-NMR(400MHz,DMSO-d 6 ):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 piperonyl derivative 1- (7-bromobenzo [ d ] [1,3] dioxol-4-yl) ethan-1-one (Compound of formula III)
Sodium hydroxide (10.8 g,0.27 mol), N-methylpyrrolidone (200 ml), dibromomethane (24.3 g,0.14 mol) were added to the reaction flask, and a solution of 2, 3-dihydroxy-4-bromoacetophenone (25 g,0.108 mol) in N-methylpyrrolidone (50 ml) was slowly added dropwise thereto, and after completion of the dropwise addition, the reaction was carried out at an internal temperature of 120℃for 4 hours. Cooled to room temperature, the pH was adjusted to about 4 with 2N hydrochloric acid, extracted with ethyl acetate (100 ml. Times.3), dried over anhydrous sodium sulfate, and the dried crude product was concentrated. 200ml of n-heptane was added thereto, the mixture was refluxed for 1 hour, cooled to room temperature and stirred for 2 hours, and then filtered and dried to obtain 20.8g of piperonyl derivative 7-bromobenzo [ D ] [1,3] dioxol-4-ethanone, the yield of which was 79.2%. The purity is 99.1%.
Experimental results: 1 H-NMR(400MHz,DMSO-d 6 ):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) ethyl-1-ketone can reach 51.7-58.8%, and the purity of the final product is higher than 99%.
In summary, the invention provides a synthesis method of piper-ring derivatives, which has the advantages of high yield, high purity, short synthesis steps, conventional and easily available starting materials, low cost and environmental friendliness, and has good industrial application prospect.
Claims (9)
1. A method for synthesizing piper-nigrum derivatives, which is characterized by comprising the following steps:
(1) The compound shown in the formula I and bromine undergo substitution reaction under the action of alkali to obtain a compound shown in the formula II; the mol ratio of the compound shown in the formula I to bromine to alkali is 1 (1-2) (2-5); the reaction conditions are as follows: reacting for 1-3 hours at-10 ℃ to-50 ℃ in an organic solvent; the base is selected from tert-butylamine, diisopropylethylamine, triethylamine, N-methylmorpholine, triethylenediamine or tetramethylethylenediamine;
(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 derivative shown in the formula III; the mol ratio of the compound shown in the formula II to dihalomethane and inorganic base is 1 (1-2) (2-5); the reaction conditions are as follows: reacting in organic solvent at 70-160 deg.c for 4-5 hr; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide, and the dihalomethane is selected from dichloromethane, dibromomethane or diiodomethane;
the reaction route is as follows:
wherein R is methyl;
the step (1) further comprises the following post-treatment steps: heating to room temperature, filtering to obtain a filter cake, adding the purifying agent A, heating and 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 petroleum ether;
the step (2) further comprises the following post-treatment steps: cooling to room temperature, regulating pH to acidity, extracting, drying, concentrating, adding purifying agent B, heating and refluxing, cooling to room temperature, stirring, filtering to obtain filter cake, and oven drying; the purifying agent B is n-heptane.
2. The synthetic method according to claim 1, wherein the organic solvent in the step (1) is selected from toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane.
3. The method of claim 1, wherein the organic solvent in step (2) is selected from the group consisting of N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, dioxane, and acetonitrile.
4. The method of claim 1, wherein the compound of formula I is obtained by reacting catechol with an acylating agent in the presence of a lewis acid.
5. The synthesis method according to claim 4, wherein the molar ratio of catechol to acylating agent and Lewis acid is 1 (1-2): 2-5, and the reaction conditions are: the reaction is carried out in an organic solvent or without adding solvent, and the reaction temperature ranges are as follows: the reaction time is 3-4 hours from room temperature to the reflux temperature of the organic solvent.
6. The method of claim 5, wherein the organic solvent is selected from the group consisting of dichloromethane, dichloroethane, nitromethane, nitrobenzene, and carbon disulfide.
7. The synthesis method according to claim 5, further comprising the following post-processing steps: quenching reaction at room temperature, extracting, separating liquid, 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 methylene dichloride.
8. The method of claim 7, wherein the purifying agent C is n-heptane.
9. The synthetic method of claim 7 wherein the quenching reaction is by the addition of water or hydrochloric acid.
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