CN103012086A - Method for preparing 2,3-dihydro-1-indanone and derivative thereof - Google Patents
Method for preparing 2,3-dihydro-1-indanone and derivative thereof Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 26
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 56
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000011780 sodium chloride Substances 0.000 claims abstract description 30
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 27
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 230000007062 hydrolysis Effects 0.000 claims abstract description 11
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 3
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 3
- 125000005843 halogen group Chemical group 0.000 claims abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 2
- 238000003756 stirring Methods 0.000 claims description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N hydrochloric acid Substances Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 7
- 239000000047 product Substances 0.000 claims description 5
- -1 methoxy, ethoxy Chemical group 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract description 10
- 238000005580 one pot reaction Methods 0.000 abstract description 9
- QNXSIUBBGPHDDE-UHFFFAOYSA-N indan-1-one Chemical compound C1=CC=C2C(=O)CCC2=C1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 5
- 238000001035 drying Methods 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 206010020751 Hypersensitivity Diseases 0.000 abstract description 3
- 208000026935 allergic disease Diseases 0.000 abstract description 3
- 230000007815 allergy Effects 0.000 abstract description 3
- 238000005917 acylation reaction Methods 0.000 abstract description 2
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000002156 mixing Methods 0.000 abstract description 2
- 238000004806 packaging method and process Methods 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract description 2
- 238000013019 agitation Methods 0.000 abstract 1
- 230000014759 maintenance of location Effects 0.000 abstract 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
- 239000000543 intermediate Substances 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 238000002844 melting Methods 0.000 description 12
- 230000008018 melting Effects 0.000 description 12
- 238000000967 suction filtration Methods 0.000 description 12
- 239000012043 crude product Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 10
- 239000005457 ice water Substances 0.000 description 10
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 230000008569 process Effects 0.000 description 5
- HWLCQLGXQGPJKA-UHFFFAOYSA-N 1,2-dichlorobenzene propan-2-one Chemical compound CC(C)=O.Clc1ccccc1Cl HWLCQLGXQGPJKA-UHFFFAOYSA-N 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
- RGVBYOCNGAHKMT-UHFFFAOYSA-N 3-oxabicyclo[3.2.2]nona-1(7),5,8-triene Chemical compound C1OCC2=CC=C1C=C2 RGVBYOCNGAHKMT-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- SNWQUNCRDLUDEX-UHFFFAOYSA-N inden-1-one Chemical compound C1=CC=C2C(=O)C=CC2=C1 SNWQUNCRDLUDEX-UHFFFAOYSA-N 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 description 2
- WVPPBVAMKNQXJA-UHFFFAOYSA-N 5-fluoro-2,3-dihydroinden-1-one Chemical compound FC1=CC=C2C(=O)CCC2=C1 WVPPBVAMKNQXJA-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 102000012440 Acetylcholinesterase Human genes 0.000 description 2
- 108010022752 Acetylcholinesterase Proteins 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000005907 Indoxacarb Substances 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- 229940022698 acetylcholinesterase Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 150000001555 benzenes Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- VBCVPMMZEGZULK-NRFANRHFSA-N indoxacarb Chemical compound C([C@@]1(OC2)C(=O)OC)C3=CC(Cl)=CC=C3C1=NN2C(=O)N(C(=O)OC)C1=CC=C(OC(F)(F)F)C=C1 VBCVPMMZEGZULK-NRFANRHFSA-N 0.000 description 2
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- 239000010457 zeolite Substances 0.000 description 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 1
- QUGUFLJIAFISSW-UHFFFAOYSA-N 1,4-difluorobenzene Chemical compound FC1=CC=C(F)C=C1 QUGUFLJIAFISSW-UHFFFAOYSA-N 0.000 description 1
- CHLICZRVGGXEOD-UHFFFAOYSA-N 1-Methoxy-4-methylbenzene Chemical compound COC1=CC=C(C)C=C1 CHLICZRVGGXEOD-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- KSONICAHAPRCMV-UHFFFAOYSA-N 5-bromo-2,3-dihydroinden-1-one Chemical compound BrC1=CC=C2C(=O)CCC2=C1 KSONICAHAPRCMV-UHFFFAOYSA-N 0.000 description 1
- MEDSHTHCZIOVPU-UHFFFAOYSA-N 5-chloro-2,3-dihydroinden-1-one Chemical compound ClC1=CC=C2C(=O)CCC2=C1 MEDSHTHCZIOVPU-UHFFFAOYSA-N 0.000 description 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940039856 aricept Drugs 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000003937 effect on alzheimer disease Effects 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011964 heteropoly acid Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
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- 238000005728 strengthening Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthetic method of indanone substances, and particularly relates to a method for preparing 2,3-dihydro-1-indanone and a derivative thereof. The method comprises the following steps of: mixing benzene substituendum of which the structure is shown in a formula (I) with AlCl3/NaCl, dropwise adding 3-chloropropionylchloride under agitation, and reacting to prepare the 2,3-dihydro-1-indanone and the derivative thereof in one step, wherein R1 and R2 are H atoms, halogen atoms, C1-C10 alkyl, methoxyl, ethyoxyl or amino; dropwise adding 3-chloropropionylchloride at 0-40 DEG C, wherein the control temperature is 0-60 DEG C and the retention time is 0.5-3hours; carrying out Fuke acylation reaction, heating to 150-200 DEG C to keep for 0.5-4hours; and carrying out cyclization reaction, and hydrolyzing cyclization reaction products, wherein the hydrolysis temperature is 50-100 DEG C. Two steps of reaction are merged into a one-pot method. Thus, purifying, drying and packaging of a midbody are reduced; the allergy possibility is avoided; the usage amount of a catalyst is reduced; and the production cost is reduced, and the environmental pollution is also reduced.
Description
Technical Field
The invention relates to a synthetic method of indenone substances, in particular to a method for preparing 2, 3-dihydro-1-indenone and derivatives thereof.
Background
The 2, 3-dihydro-1-indanone is an important chemical raw material with simple structure and wide application, and is an important intermediate for synthesizing various medicines and pesticides. Various indenone structures with different structures are widely present in natural products separated from plants and marine organisms. Many compounds containing indanone structure show various physiological and pharmacological activities, including antitumor activity and acetylcholinesterase (acetylcholinesterase) inhibition activity, and for example, the famous compound (aricept) has good curative effect on Alzheimer's disease. Some indenones have been produced industrially, such as 5-fluoro-2, 3-dihydro-1-indenone, 5-bromo-2, 3-dihydro-1-indenone, and 5-chloro-2, 3-dihydro-1-indenone, which are in great industrial demand. Wherein the 5-chloro-2, 3-dihydro-1-indanone is a key intermediate of an agricultural chemical widely used in the world, namely indoxacarb (indoxacarb).
In order to reduce cost and protect the environment, many attempts are made to improve the synthesis of 2, 3-dihydro-1-indanone. Currently, there are two major routes to the synthesis of 2, 3-dihydro-1-indanones. The first route is that substituted benzaldehyde is used as a starting material, and the corresponding 2, 3-dihydro-1-indanone is obtained through five-step reaction including condensation with diethyl malonate, hydrolysis, decarboxylation, hydrogenation reduction and cyclization (EP 549900). The main disadvantages of this route are too many reaction steps (5 steps), difficult raw material sources, long cycle, high cost, etc.
The second route uses substituted benzene as the starting material, which is reacted with 3-chloropropionyl chloride in AlCl3Carrying out Friedel-crafts acylation reaction under the action of the acetone to obtain corresponding 3-chloro- (substituted benzene) acetone, purifying and drying the intermediate, and then mixing with AlCl3Intramolecular para-alkylation cyclization was carried out to give the corresponding 2, 3-dihydro-1-indanone (EP545304, CN 1403434A). The process has short route and low cost, and is widely adopted by the industry at present. However, the products of the first step, such as 3-chloro- (4-chlorobenzene) acetone, cause strong allergic phenomena, and the purification intermediates often use large amounts of petroleum ether, which easily causes a workshop fire.
In addition to the main production routes described above, the literature reports several other synthetic routes, such as acylation, intramolecular alkylation to give the corresponding 2, 3-dihydro-1-indanone using strong acids (concentrated sulfuric acid, trifluoromethanesulfonic acid, chlorosulfonic acid, etc.) as catalysts for the Friedel-crafts reaction (FR2784986, WO 2015961). Other synthetic routes include the use of precious metal catalysts (Pd, Tb (OTf))3Etc.), zeolites (zeolite), heteropolyacids (heteropolyacid), etc. These methods cannot be applied to production for reasons of cost, environmental protection, industrial operability, and the like.
Although 5-chloro-2, 3-indanone is an important intermediate for medicine and pesticide, the production thereof still has major obstacles including environmental protection and cost. First, the current production of 5-chloro-2, 3-indanone requires the use of about 7 times the molar amount of AlCl3The reaction at high temperature produces a large amount of HCl gas. First, theSecondly, the 3-chloro- (4-chlorobenzene) acetone as the first step intermediate is a strong allergic substance, and the intermediate must be purified and dried before entering the next step of reaction. Third, the purification of the first step intermediate requires the use of large amounts of petroleum ether, which is a fire hazard. Fourth, the second step of the cyclization reaction requires the addition of the first step intermediate to preheated AlCl at 120 deg.C3And NaCl, a large amount of HCl gas evolved. Fifth, the second step requires melting reaction under heating at 180 deg.C with a large amount of AlCl3Sublimed to easily block the pipeline of the reaction kettle.
Disclosure of Invention
The invention aims to overcome the problems and provides a method for preparing 2, 3-dihydro-1-indanone and derivatives thereof.
The method for preparing the 2, 3-dihydro-1-indanone and the derivatives thereof comprises the following steps:
benzene substituent with the structure shown as formula (II) and AlCl3NaCl, dropwise adding 3-chloropropionyl chloride while stirring, sequentially carrying out Friedel-crafts acylation reaction, cyclization reaction and hydrolysis in a reactor, and carrying out one-step reaction treatment to obtain 2, 3-dihydro-1-indanone and derivatives thereof, wherein the structural formula is shown as a formula (I);
wherein R1 and R2 are H, halogen atoms, C1-C10 alkyl, methoxy, ethoxy or amino, R1 and R2 can jointly form a ring structure with a benzene ring parent, and the like;
dropwise adding 3-chloropropionyl chloride at 0-40 ℃, controlling the temperature to be 0-60 ℃ and keeping the temperature for 0.5-3 h, carrying out a Friedel-crafts acylation reaction, heating to 150-200 ℃ and keeping the temperature for 0.5-4 h, carrying out a cyclization reaction, and hydrolyzing the cyclization reaction product at 50-100 ℃.
In the invention, through the reaction of AlCl3Is added into a reactor under the action of the (A), and is obtained by carrying out one-pot method through Friedel-crafts acylation and Friedel-crafts alkylation, and the reaction is shown in a reaction formula I.
According to the method for preparing 2, 3-dihydro-1-indanone and derivatives thereof,
the molar ratio of the benzene substituent with the structural formula of formula (II) to the 3-chloropropionyl chloride is 1: 1-1.2, preferably 1: 1-1.1, and more preferably 1: 1-1.05;
the structural formula is benzene substituent and AlCl of formula (II)3The mol ratio of NaCl to NaCl is 1: 2-4: 1-2, preferably 1: 2-3: 1-2, more preferably 1: 2-2.5: 1-1.5,
the dropping temperature of the 3-chloropropionyl chloride is 0-40 ℃; preferably 0 to 30 ℃, and more preferably 10 to 20 ℃;
the temperature of the friedel-crafts acylation reaction is 0-60 ℃, the time is 0.5-3 h, and preferably 0.5-1 h;
the temperature of the cyclization reaction is 150-200 ℃, the preferable temperature is 150-190 ℃, the more preferable temperature is 155-175 ℃, the time is 0.5-4 h, the preferable time is 1-1.5 h,
the hydrolysis temperature is 50-100 ℃, preferably 60-80 ℃, and more preferably 65-75 ℃.
According to the method for preparing the 2, 3-dihydro-1-indanone and the derivatives thereof, the hydrolysis is carried out by adding the product obtained by the reaction into ice-hydrochloric acid.
According to an embodiment of the present invention, the specific preparation method comprises: inverse directionThe temperature is controlled within the range of 0-200 ℃, and the reaction one-pot method is carried out in three stages: in the first stage, the starting materials (substituted benzene) and AlCl3NaCl, and dropwise adding 3-chloropropionyl chloride while stirring. The reaction temperature is controlled to be 0-60 ℃, and the dripping temperature is controlled to be 0-40 ℃, preferably 0-30 ℃, and more preferably 10-20 ℃. And in the second stage, heating to 150-200 ℃ under stirring to react for 30-120 minutes. The reaction temperature is preferably 150 to 190 ℃, and more preferably 155 to 175 ℃. And in the third stage, after the reaction is finished, pouring the reaction liquid into ice-hydrochloric acid for hydrolysis, separating out a product, performing suction filtration, drying, decoloring by using activated carbon, and recrystallizing to obtain a qualified product. Wherein the hydrolysis temperature is controlled to be 50-100 ℃, preferably 60-80 ℃, and more preferably 65-75 ℃.
The invention has the advantages of simple operation, low raw material cost, low equipment occupancy rate and less personnel investment. Compared with any method adopted before, the method does not use organic solvent in the reaction process, thereby reducing the cost and the pollution to the environment. The process of the invention does not need to separate and purify the intermediate (3-chloro- (4-chlorobenzene) acetone) obtained by the first-step reaction with strong allergy, thereby strengthening the protection of the health of workers. The process of the present invention can be used to prepare many other substituted 2, 3-dihydro-1-indanones with general applicability.
In the invention, the 2, 3-dihydro-1-indanone and the derivatives thereof are prepared by one-pot method. The one-pot method is the most valuable and widely expected method for organic synthesis, especially industrial production. However, due to the complexity of the organic reactions and the difficulty of process design, not many reactions are possible that can be carried out in a one-pot process. The invention is well designed, a great deal of experiments are carried out on the temperature and the time of each step of reaction and the molar ratio among all the substances, and a feasible production process route is obtained on the basis of continuous summary. The process provided by the invention requires the reaction conditions such as temperature, raw materials and catalysts (benzene substitutes, 3-chloropropionyl chloride, AlCl) in the preparation process3NaCl, etc.), time, hydrolysis, etc., under strict control,the side reaction is reduced, and the final product of the reaction has higher purity.
According to the method for preparing 2, 3-dihydro-1-indanone and derivatives thereof, only 2-3 times of molar amount of AlCl is needed to be used in the invention3Significantly reduces AlCl3The sublimation and the release of HCl gas, and the pipeline blockage is effectively avoided. In addition, the invention combines two-step reaction into one pot, and does not need to add an intermediate into a reaction system at high temperature, thereby eliminating the damage of the intermediate to human bodies and avoiding the release of a large amount of HCl gas to the surrounding environment.
The invention provides a new process for preparing 2, 3-dihydro-1-indanone and derivatives thereof. The invention combines two-step reaction and one-pot method, thereby reducing the purification, drying and packaging of the intermediate, avoiding the possibility of allergy, reducing the usage amount of the catalyst, simplifying the operation, reducing the production cost, reducing the environmental pollution and protecting the health of workers.
Detailed Description
EXAMPLE 1 preparation of 5-chloro-2, 3-dihydro-1-indanone
Adding chlorobenzene (200g, 1.78mol), aluminum trichloride (670g, 5mol) and NaCl (110g, 1.88mol) into a 1L three-neck flask, stirring, dropwise adding 3-chloropropionyl chloride (237g, 1.87mol) at 25-35 ℃, wherein the molar ratio of chlorobenzene to 3-chloropropionyl chloride is 1: 1.1, the molar ratio of chlorobenzene to aluminum trichloride to NaCl is 1: 2.8: 1.1, the dropwise adding temperature is room temperature, stirring for 1 hour at 45-65 ℃, heating to 150-165 ℃, reacting for 1 hour, cooling to 80-100 ℃, pouring into 2kg of ice water hydrochloric acid, and performing suction filtration to obtain 335g of crude product, recrystallizing to obtain 219.5g of solid with the yield of 74% (purity of 98%) and the melting point of 97-98 ℃.
HNMR(ppm，CDCl3)7.68-7.71(m，1H)，7.45-7.49(m，1H)，7.36-7.38(m，1H)，3.13-3.16(t，2H)，2.71-2.74(t，2H)。
EXAMPLE 2 preparation of 5-bromo-2, 3-dihydro-1-indanone
Bromobenzene (100g, 0.64mol), aluminum trichloride (212.5g, 1.6mol) and NaCl (37g, 0.64mol) are added into a 1L three-neck flask, stirred, 3-chloropropionyl chloride (83g, 0.65mol) is dropwise added at 20-30 ℃, the molar ratio of bromobenzene to 3-chloropropionyl chloride is 1: 1, the molar ratio of bromobenzene to aluminum trichloride to NaCl is 1: 2.5: 1, stirred for 30 minutes at 50-70 ℃, stirred for 1 hour at 160-165 ℃, cooled to 70-80 ℃, poured into 1kg of ice water hydrochloric acid, and subjected to suction filtration to obtain 107g of crude product, and recrystallized to obtain 85g of solid with the yield of 63% (the purity is more than 98%) and the melting point of 127-128 ℃.
HNMR(ppm，CDCl3)7.59-7.64(m，2H)，7.48-7.51(m，1H)，3.09-3.12(t，2H)，2.66-2.69(t，2H)。
EXAMPLE 3 preparation of 5-fluoro-2, 3-dihydro-1-indanone
Adding fluorobenzene (96g, 1mol), aluminum trichloride (333g, 2.5mol) and NaCl (65g, 1.1mol) into a 1L three-neck flask, stirring, dropwise adding 3-chloropropionyl chloride (133g, 1.05mol) at 0-10 ℃, stirring for 3-chloropropionyl chloride at a molar ratio of 1: 1.1, fluorobenzene to 3-chloropropionyl chloride at a molar ratio of 1: 2.5: 1.1, stirring for 2 hours at 65-70 ℃, stirring for 3 hours at 165-175 ℃, cooling to 75-80 ℃, pouring into 1kg of ice water hydrochloric acid, performing suction filtration to obtain 134g of crude product, recrystallizing to obtain 84g of solid, wherein the yield is 56% (purity is more than 98%), and the melting point is 38-39 ℃.
HNMR(ppm，CDCl3)7.75-7.78(m，1H)，7.57-7.59(m，1H)，7.42-7.45(m，1H)，3.17-3.20(t，2H)，2.85-2.87(t，2H)。
EXAMPLE 4 preparation of 5-methyl-2, 3-dihydro-1-indanone
Adding toluene (100g, 1.08mol), aluminum trichloride (405g, 3.05mol) and NaCl (70g, 1.2mol) into a 1L three-neck flask, stirring, dropwise adding 3-chloropropionyl chloride (140g, 1.1mol) at the temperature of 5-15 ℃, stirring for 120 minutes at the temperature of 170-180 ℃, cooling to 75-85 ℃, pouring into 1kg of ice water hydrochloric acid, performing suction filtration to obtain a crude product 144g, and recrystallizing to obtain a solid 114g, wherein the yield is 72 percent (the purity is more than 98 percent), and the melting point is 73-74 ℃.
HNMR(ppm，CDCl3)7.42-7.45(m，1H)，7.03-7.05(m，1H)，6.83-6.85(m，1H)，2.74-2.76(m，1H)，2.55-2.57(t，2H)，2.43(s，3H)。
EXAMPLE 5 preparation of 5-methoxy-2, 3-dihydro-1-indanone
Adding anisole (108g, 1mol), aluminum trichloride (346g, 2.6mol) and NaCl (60g, 1mol) into a 1L three-neck flask, stirring, dropwise adding 3-chloropropionyl chloride (130g, 1.02mol) at 15-25 ℃, wherein the molar ratio of anisole to 3-chloropropionyl chloride is 1: 1.02, the molar ratio of anisole to aluminum trichloride to NaCl is 1: 2.6: 1, stirring for 30 minutes at 35-65 ℃, stirring for 1 hour at 165-170 ℃, cooling to 70-80 ℃, pouring into 1kg of ice water hydrochloric acid, performing suction filtration to obtain a crude product 137g, recrystallizing to obtain 79.5g of a solid, the yield is 49%, and the melting point is 109-110 ℃.
HNMR(ppm，CDCl3)7.69-7.71(m，1H)，6.94-6.96(m，2H)，3.89(s，3H)，3.08-3.11(t，2H)，2.67-2.70(t，2H)。
Example 6 preparation of 5, 7-difluoro-2, 3-dihydro-1-indanone
Adding m-difluorobenzene (57g, 0.5mol), aluminum trichloride (200g, 1.5mol) and NaCl (58g, 1mol) into a 1-liter three-neck flask, stirring, dropwise adding 3-chloropropionyl chloride (70g, 0.55mol) at the temperature of 30-40 ℃, stirring for 4 hours at the temperature of 190-200 ℃, cooling to 55-60 ℃, pouring into 1kg of ice water hydrochloric acid, and performing suction filtration to obtain 67g of a crude product, wherein the yield of 51g of a solid is 61%, and the melting point of 85-86 ℃.
HNMR(ppm，CDCl3)7.01(s，1H)，6.79(s，1H)，3.14-3.17(t，2H)，2.73-2.76(t，2H)。
EXAMPLE 7 preparation of 5, 6-dimethoxy-2, 3-dihydro-1-indanone
Adding phthalic ether (138g, 1mol), aluminum trichloride (280g, 2.1mol) and NaCl (65g, 1.1mol) into a 1L three-neck flask, stirring, dropwise adding 3-chloropropionyl chloride (134g, 1.05mol) at 0-10 ℃, stirring for 0.5 hour at 10-30 ℃, stirring for 0.5 hour at 150-160 ℃, cooling to 70-75 ℃, pouring into 1kg of ice water hydrochloric acid, performing suction filtration to obtain a crude product 164g, recrystallizing to obtain a solid 142g, wherein the yield is 74%, and the melting point is 119-120 ℃.
HNMR(ppm，CDCl3)7.17(s，1H)，6.89(s，1H)，3.96(s，3H)，3.90(s，3H)，3.03-3.06(t，2H)，2.65-2.68(t，2H)。
Example 8 preparation of 4, 7-difluoro-2, 3-dihydro-1-indanone
Adding para-difluorobenzene (57g, 0.5mol), aluminum trichloride (267g, 2mol) and NaCl (58g, 1mol) into a 1-liter three-neck flask, stirring, dropwise adding 3-chloropropionyl chloride (76g, 0.6mol) at 30-40 ℃, dropwise adding difluorobenzene and 3-chloropropionyl chloride at a molar ratio of 1: 1.2, difluorobenzene, aluminum trichloride and NaCl at a molar ratio of 1: 4: 2, stirring at 50-55 ℃ for 3 hours, stirring at 175-195 ℃ for 4 hours, cooling to 55-60 ℃, pouring into 1kg of ice water hydrochloric acid, and performing suction filtration to obtain 65g of crude product, recrystallizing to obtain 44g of solid, wherein the yield is 52%, and the melting point is 126-128 ℃.
HNMR(ppm，CDCl3)7.23-7.25(m，1H)，7.02-7.04(t，1H)，3.07-3.10(t，2H)，2.79-2.81(t，2H)
Example 9 preparation of 4-methyl-7-methoxy-2, 3-dihydro-1-indanone
Adding p-methylanisole (61g, 0.5mol), aluminum trichloride (134g, 1mol) and NaCl (58g, 1mol) into a 1-liter three-neck flask, stirring, dropwise adding 3-chloropropionyl chloride (64g, 0.5mol) at 15-30 ℃, stirring for 2 hours at 20-30 ℃, stirring for 3 hours at 150-160 ℃, cooling to 50-60 ℃, pouring into 0.5kg of ice water hydrochloric acid, and performing suction filtration to obtain 71g of crude product, recrystallizing to obtain 56g of solid, wherein the yield is 64%, and the melting point is 107-110 ℃.
HNMR(ppm，CDCl3)7.03-7.05(m，1H)，6.89-6.91(m，1H)，3.87(s，3H)，2.96-2.99(t，2H)，2.62-2.65(t，2H)，2.55(s，3H)。
EXAMPLE 10 preparation of 4, 7-dimethoxy-2, 3-dihydro-1-indanone
Adding p-xylylene ether (138g, 1mol), aluminum trichloride (267g, 2mol) and NaCl (70g, 1.2mol) into a 1L three-neck flask, stirring, dropwise adding 3-chloropropionyl chloride (130g, 1.02mol) at 0-10 ℃, wherein the molar ratio of the p-xylylene ether to the 3-chloropropionyl chloride is 1: 1.02, the molar ratio of the p-xylylene ether to the aluminum trichloride to the NaCl is 1: 2: 1.2, stirring for 1 hour at 0-30 ℃, stirring for 3 hours at 150-155 ℃, cooling to 80-85 ℃, pouring into 1kg of ice water hydrochloric acid, performing suction filtration to obtain a crude product 151g, recrystallizing to obtain 113g of a solid, wherein the yield is 59%, and the melting point is 97-100 ℃.
HNMR(ppm，CDCl3)6.98-7.00(d，1H)，6.79-6.81(d，1H)，3.88(s，3H)，3.84(s，3H)，3.02-3.05(t，2H)，2.69-2.72(t，2H)。
Example 11 preparation of 4, 7-dimethyl-2, 3-indanone
Adding 53g of p-xylene (0.5 mol), 166g of aluminum trichloride (1.25 mol) and 40g of NaCl (0.68 mol) into a 1L three-neck flask, stirring, dropwise adding 70g of 3-chloropropionyl chloride (0.55 mol) at 10-20 ℃, stirring for 90 minutes at 30-50 ℃, stirring for 2 hours at 170-180 ℃, cooling to 50-60 ℃, pouring into 0.5kg of hydrochloric acid, performing suction filtration to obtain 74g of crude product, recrystallizing to obtain 62g of solid, wherein the yield is 78%, and the melting point is 128-130 ℃.
HNMR(ppm，CDCl3)7.23-7.25(d，1H)，7.00-7.02(d，1H)，2.93-2.95(t，2H)，2.64-2.66(t，2H)，2.64(s，3H)，2.34(s，3H)。
Claims (5)
1. A process for preparing 2, 3-dihydro-1-indanone and derivatives thereof, comprising the steps of:
benzene substituent with the structure shown as formula (II) and AlCl3NaCl, dropwise adding 3-chloropropionyl chloride while stirring, and reacting in one step to obtain 2, 3-dihydro-1-indanone and derivatives thereof;
wherein,
r1, R2 is H atom, halogen atom, C1-C10 alkyl, methoxy, ethoxy or amino;
dropwise adding 3-chloropropionyl chloride at 0-40 ℃, controlling the temperature to be 0-60 ℃ and keeping for 0.5-3 h, carrying out a Friedel-crafts acylation reaction, heating to 150-200 ℃ and keeping for 0.5-4 h, carrying out a cyclization reaction, and hydrolyzing the cyclization reaction product at 50-100 ℃.
2. The process for preparing 2, 3-dihydro-1-indanone and derivatives thereof according to claim 1,
the molar ratio of the benzene substituent with the structural formula of formula (II) to the 3-chloropropionyl chloride is 1: 1-1.2,
the structural formula is benzene substituent and AlCl of formula (II)3The mol ratio of NaCl to NaCl is 1: 2-4: 1-2.
3. The process for preparing 2, 3-dihydro-1-indanone and derivatives thereof according to claim 1,
the structure is that the molar ratio of the benzene substituent shown in the formula (II) to the 3-chloropropionyl chloride is 1: 1-1.1,
the structure is benzene substituent and AlCl shown as a formula (II)3The mol ratio of NaCl to NaCl is 1: 2-3: 1-2,
the dropping temperature of the 3-chloropropionyl chloride is 0-30 ℃;
the time of the Friedel-crafts acylation reaction is 0.5 to 1 hour,
the temperature of the cyclization reaction is 150-190 ℃, the time is 1-1.5 h,
the hydrolysis temperature is 60-80 ℃.
4. The process for preparing 2, 3-dihydro-1-indanone and derivatives thereof according to claim 1 or 3,
the structure is that the molar ratio of the benzene substituent shown in the formula (II) to the 3-chloropropionyl chloride is 1: 1-1.05;
the structure is benzene substituent and AlCl shown as a formula (II)3The mol ratio of NaCl to NaCl is 1: 2-2.5: 1-1.5,
the dropping temperature of the 3-chloropropionyl chloride is 10-20 ℃;
the temperature of the cyclization reaction is 155-175 ℃,
the hydrolysis temperature is 65-75 ℃.
5. The method for preparing 2, 3-dihydro-1-indanone and derivatives thereof according to claim 1, wherein the hydrolysis is performed by adding the product obtained by the cyclization reaction to ice-hydrochloric acid.
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| CN105237416A (en) * | 2015-10-14 | 2016-01-13 | 湖南华腾制药有限公司 | Synthesis method of 5-aminoindanone |
| CN108558627A (en) * | 2018-05-04 | 2018-09-21 | 山西大学 | A method of preparing 5- hydroxide radical-1-indenones |
| CN109534971A (en) * | 2018-11-05 | 2019-03-29 | 宿迁市科莱博生物化学有限公司 | 5- chlorine indone process units and its production method |
| CN109574815A (en) * | 2018-11-27 | 2019-04-05 | 江苏师范大学 | A kind of preparation method of intermediate 5- bromindion |
| CN110283059A (en) * | 2019-06-06 | 2019-09-27 | 无锡合全药业有限公司 | A kind of -1 hydrogen of fluoro- 5- hydroxyl -2,3- dihydro of 7- -1-Indanone synthetic method |
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| CN112457179A (en) * | 2020-12-04 | 2021-03-09 | 阜新睿光氟化学有限公司 | Preparation method of 5-chloro-1-indanone |
| CN112939755A (en) * | 2021-01-27 | 2021-06-11 | 南开沧州渤海新区绿色化工研究有限公司 | Novel process for preparing 5-chloro-2, 3-dihydro-1-indanone |
| CN113651784A (en) * | 2021-08-30 | 2021-11-16 | 大连新阳光材料科技有限公司 | Synthetic method of 3,3',4,4' -biphenyl tetracarboxylic dianhydride |
| CN116143602A (en) * | 2022-12-20 | 2023-05-23 | 西南大学 | Indenone and indazolone derivatives with antioxidant activity, and synthetic method and application thereof |
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