CN103804294B - Synthetic method of 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one - Google Patents
Synthetic method of 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one Download PDFInfo
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- CN103804294B CN103804294B CN201410035968.8A CN201410035968A CN103804294B CN 103804294 B CN103804294 B CN 103804294B CN 201410035968 A CN201410035968 A CN 201410035968A CN 103804294 B CN103804294 B CN 103804294B
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims description 35
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 25
- 239000001257 hydrogen Substances 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 17
- 239000012074 organic phase Substances 0.000 claims description 16
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 14
- BLNVISNJTIRAHF-UHFFFAOYSA-N 4-chlorobenzamide Chemical compound NC(=O)C1=CC=C(Cl)C=C1 BLNVISNJTIRAHF-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 9
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims description 5
- 239000008346 aqueous phase Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 239000012266 salt solution Substances 0.000 claims description 5
- 238000006856 Wolf-Kishner-Huang Minlon reduction reaction Methods 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract description 2
- 229910000510 noble metal Inorganic materials 0.000 abstract description 2
- 238000006722 reduction reaction Methods 0.000 abstract description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 abstract 1
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 abstract 1
- 238000006898 Intramolecular Friedel-Crafts reaction Methods 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 229940014800 succinic anhydride Drugs 0.000 abstract 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- UPSNSRKMOHOEEO-UHFFFAOYSA-N 4-(4-chloroanilino)-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NC1=CC=C(Cl)C=C1 UPSNSRKMOHOEEO-UHFFFAOYSA-N 0.000 description 2
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical group NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005649 metathesis reaction Methods 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- RZPFVRFSYMUDJO-UHFFFAOYSA-N 2h-naphthalen-1-one Chemical compound C1=CC=C2C(=O)CC=CC2=C1 RZPFVRFSYMUDJO-UHFFFAOYSA-N 0.000 description 1
- GWHPLVIIGOTUJS-UHFFFAOYSA-N 4-(2-chloroanilino)-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NC1=CC=CC=C1Cl GWHPLVIIGOTUJS-UHFFFAOYSA-N 0.000 description 1
- 238000006237 Beckmann rearrangement reaction Methods 0.000 description 1
- RREGPCQVUJXAFB-UHFFFAOYSA-N CC(CC(c1cc(Cl)ccc1N1)=O)C1=O Chemical compound CC(CC(c1cc(Cl)ccc1N1)=O)C1=O RREGPCQVUJXAFB-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- WXZRWXDXKODMJY-UHFFFAOYSA-N O=C(CCC1)Nc(cc2)c1cc2Cl Chemical compound O=C(CCC1)Nc(cc2)c1cc2Cl WXZRWXDXKODMJY-UHFFFAOYSA-N 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000005865 alkene metathesis reaction Methods 0.000 description 1
- 125000000746 allylic group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000011984 grubbs catalyst Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NPSSWQJHYLDCNV-UHFFFAOYSA-N prop-2-enoic acid;hydrochloride Chemical compound Cl.OC(=O)C=C NPSSWQJHYLDCNV-UHFFFAOYSA-N 0.000 description 1
- WLHPCEJPGLYEJZ-UHFFFAOYSA-N prop-2-enyltin Chemical compound [Sn]CC=C WLHPCEJPGLYEJZ-UHFFFAOYSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 108010064245 urinary gonadotropin fragment Proteins 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the organic synthesis field and specifically relates to a synthetic method of 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one. The synthetic method is used for solving the technical problems that the existing synthetic method is low in yield, high in cost, difficult in aftertreatment purification, difficult in raw material getting and not applicable to enlarged production. The technical scheme for solving the technical problem is to provide the synthetic method of 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one, and the synthetic method comprises the steps of reacting o- or para-chloroaniline with succinic anhydride, carrying out intramolecular Friedel-Craft ring closing reaction of the reaction product, and then carrying out Huangminglong reduction reaction to obtain the 7 or 9-chloro-4,5-dihydro-1hydro-benzo[b]azepine-2(3hydro)-one. The invention provides a new method which is short in steps, high in total yield and free of use of expensive noble metal catalyst.
Description
Technical field
The invention belongs to organic synthesis field, be specifically related to the synthetic method of 7 or chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of 9-.
Background technology
Azatropylidene-2-ketone is widely used in new drug development as the core fragment of Na-ion channel blocker medicine according to the literature.Especially 7 or 9 chloro-dihydrobenzo [b] azatropylidene-2-ketone can realize to drug molecule as the functional group continuing to participate in reaction due to chlorine multiple modification, and it applies extensive especially in new drug development.But mostly the synthetic method of this compounds is to become oxime rearrangement to realize with azido-or azanol by naphthalenone at present, and the use of azido-exists dangerously explosive danger, and the method for resetting often has isomer to produce, separation difficulty, and cost is very high simultaneously.Another method first builds the allylic fragrant acrylamide structure in ortho position, then close ring by the metathesis of alkene, the more saturated double bond of hydrogenation obtains target product, but to there is raw material in the method be not easy to obtain, total recovery is low, and with the noble metal catalyst of rare costliness.
The first reported scheme be by, chloro-3,4-dihydronaphthalene-1 (2 hydrogen)-one of 6-are set out, and oxammonium hydrochloride reaction generate oxime; Then reset through Beckmann and obtain chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of 7-(see Journal of OrganicChemistry; Vol.76; Nb.12; (2011); P.5123-5131).But there is following problem in the method: (1) Beckmann resets and inherently has isomer appearance, target compound reaction isomer ratios almost 1:1(52%:47% to we need), this will reduce yield greatly, make separation and purification very difficult simultaneously, produce amplification efficiency low; (2) polyphosphoric acid (PPA) or the vitriol oil will be used, unfriendly to environment; (3) program use chloro-3,4-dihydronaphthalene-1 (2 hydrogen)-one of initial feed 6-expensive, be not easy to obtain, often to be reacted more than five steps by tetraline and just can obtain.Its reaction formula is as follows:
The reported scheme of the second is with 2,6 or 2, and 4 have the aniline of different halogen substiuted to be that starting raw material is (see Tetrahedron Letters; Vol.50; Nb.17; (2009); P.1911-1913).First be the aniline that active high halogen and allyltin reagent linked reaction obtain 2 allyl groups replacements; Then amino and acrylate chloride generation acylation reaction obtains acrylamide product; Then there is the metathesis ring closure reaction of alkene in two ethylene linkages under Grubbs catalyst action, obtains the azatropylidene-2-ketone being with double bond; Finally by reduction such as hydrogenations, double bond is saturated, obtain 7 or fluoro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of 9-.There is following problem in the method: (1) starting raw material is not easy to obtain, and two ortho positions amino on phenyl ring or ortho para want diverse halogen substiuted, and synthesis ratio is more difficult; (2) coupling of the first step tin reagent and olefin metathesis ring closure reaction all will use expensive catalyzer; (3) when last double-bond hydrogenation is saturated, likely simultaneously by the halogen displacement Cheng Qing of 7 or 9.Program total recovery is very low, and waste production is excessive, is not suitable for amplifying producing.Its reaction formula is as follows:
Summary of the invention
The technical problem to be solved in the present invention is that existing synthetic method yield is low, cost is high, aftertreatment purification difficult, and raw material is not easy to obtain, and is not suitable for amplifying producing.
The scheme that the present invention solves the problems of the technologies described above is to provide the synthetic method of a kind of 7 or chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of 9-.The synthetic route of the method is as follows: Ortho-Chloro aniline or p-Chlorobenzoic acid amide and Succinic anhydried are reacted, and obtains 4-(2 or 4-chloroanilino)-4-ketobutyric acid; 4-(2 or 4-chloroanilino)-4-ketobutyric acid, by Friedel-Crafts reaction (Friedel-Crafts reaction) in molecule, obtains 7 or chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone of 9-; 7 or chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone of 9-through Huang Min-lon reduction, obtain 7 or chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of 9-.
Wherein, above-mentioned 7 or the structural formula of chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of 9-as follows:
Above-mentioned 7 or the reaction formula of synthetic method of chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of 9-as follows:
Above-mentioned 7 or the synthetic method of chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of 9-, comprise following operation steps:
A, Ortho-Chloro aniline or p-Chlorobenzoic acid amide and Succinic anhydried react: be dissolved in organic solvent by Ortho-Chloro aniline or p-Chlorobenzoic acid amide and Succinic anhydried, then heating reflux reaction 4 ~ 8 hours, reaction terminates rear removing organic solvent, adds the hydrochloric acid of cold 1N, stir 10 ~ 15 minutes in resistates; Filter out solid, obtain 4-(2 or 4-chloroanilino)-4-ketobutyric acid;
Friedel-Crafts reaction in B, molecule: above-mentioned 4-(2 or 4-chloroanilino)-4-ketobutyric acid is dissolved in ethylene dichloride, adds aluminum trichloride (anhydrous), then 55 ~ 70 degree of reactions 4 ~ 6 hours; Then by above-mentioned reaction solution cool to room temperature, control temperature is no more than 35 degree, adds the hydrochloric acid of 3N ~ 6N; Separatory retains organic phase again, and then aqueous phase ethylene dichloride extracts, and merges organic phase, organic phase after drying, solids removed by filtration, organic phase is concentrated except desolventizing, obtains 7 or chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone of 9-;
C, Huang Min-lon reduction: by 7 or 150 ~ 170 degree of reactions 4 ~ 6 hours in ethylene glycol of chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone of 9-, hydrazine hydrate and potassium hydroxide; Then reaction solution is down to room temperature, adds salt solution, filter and obtain 7 or chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of 9-.
Wherein, the mol ratio of the Ortho-Chloro aniline described in steps A or p-Chlorobenzoic acid amide and Succinic anhydried is 1:0.95 ~ 1.05.
Wherein, the organic solvent described in steps A is any one in ethylene dichloride, tetrahydrofuran (THF) or glycol dimethyl ether.
Wherein, 4-described in step B (2 or 4-chloroanilino)-4-ketobutyric acid and anhydrous AlCl
3mol ratio be 1:1.0 ~ 1.5.
Wherein, the mol ratio of chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone of 7 described in step C or 9-, hydrazine hydrate and potassium hydroxide is 1:5.0 ~ 7.0:1.3 ~ 1.8.
The present invention for starting raw material, just can obtain 7 or 9-chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one by means of only 3 steps reactions with Ortho-Chloro aniline that is cheap, that be easy to get or p-Chlorobenzoic acid amide and Succinic anhydried.Preparation method provided by the invention avoids the isomeric side-product of Beckmann rearrangement, and yield is high, simple to operate, and total recovery is higher, and product is purified convenient, and cost is lower, is applicable to suitability for industrialized production.
Specific embodiment
7 or the synthetic method of chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of 9-, comprise following operation steps:
A, Ortho-Chloro aniline or p-Chlorobenzoic acid amide and Succinic anhydried react: be dissolved in organic solvent by Ortho-Chloro aniline or p-Chlorobenzoic acid amide and Succinic anhydried, then heating reflux reaction 4 ~ 8 hours, reaction terminates rear removing organic solvent, adds the hydrochloric acid of cold 1N, stir 10 ~ 15 minutes in resistates; Filter out solid, obtain 4-(2 or 4-chloroanilino)-4-ketobutyric acid;
Friedel-Crafts reaction in B, molecule: above-mentioned 4-(2 or 4-chloroanilino)-4-ketobutyric acid is dissolved in ethylene dichloride, adds anhydrous AlCl
3, then 55 ~ 70 degree of reactions 4 ~ 6 hours; Then by above-mentioned reaction solution cool to room temperature, control temperature is no more than 35 degree, adds the hydrochloric acid of 3N ~ 6N; Separatory retains organic phase again, and then aqueous phase ethylene dichloride extracts, and merges organic phase, organic phase after drying, solids removed by filtration, organic phase is concentrated except desolventizing, obtains 7 or chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone of 9-;
C, Huang Min-lon reduction: by 7 or 150 ~ 170 degree of reactions 4 ~ 6 hours in ethylene glycol of chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone of 9-, hydrazine hydrate and potassium hydroxide; Then reaction solution is down to room temperature, adds salt solution, filter and obtain 7 or chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of 9-.
Wherein, the mol ratio of the Ortho-Chloro aniline described in steps A or p-Chlorobenzoic acid amide and Succinic anhydried is 1:0.95 ~ 1.05.When the mol ratio of Ortho-Chloro aniline or p-Chlorobenzoic acid amide and Succinic anhydried is in above-mentioned scope, raw material just reacts completely, and product purity is higher.
Wherein, the organic solvent described in steps A is any one in ethylene dichloride, tetrahydrofuran (THF) or glycol dimethyl ether.
Wherein, 4-described in step B (2 or 4-chloroanilino)-4-ketobutyric acid and anhydrous AlCl
3mol ratio be 1:1.0 ~ 1.5.AlCl
3be less than 1.0 equivalent reactions not complete, have impurity more than 1.5 equivalents and generate.
Wherein, the mol ratio of chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone of 7 described in step C or 9-, hydrazine hydrate and potassium hydroxide is 1:5.0 ~ 7.0:1.3 ~ 1.8.Hydrazine hydrate is less than 5 equivalents and stirs difficulty, does not have impact after being greater than 7 equivalents on reaction, but uneconomical; It is not complete that potassium hydroxide is less than 1.3 equivalent reactions, do not affect after being greater than 1.8 equivalents on reaction, but uneconomical.
The synthesis of chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of embodiment 17-:
(1) 127g4-chloroaniline and 100g Succinic anhydried are dissolved in 600ml ethylene dichloride, heating reflux reaction 6 hours.Remove ethylene dichloride under reduced pressure after reaction terminates, in resistates, add the hydrochloric acid of the cold 1N of 300mL, stir 10 minutes; Filter to obtain white solid 4-(4-chloroanilino)-4-ketobutyric acid 212g, yield 93.4%.H
1NMR(300MHz,DMSO-d6):δ2.61(m,4H),7.39～7.45(d,J=7.2Hz,2H),7.55～7.48(d,J=7.2Hz,2H),10.05(br,1H),11.98(br,1H)。
(2) 200g4-(4-chloroanilino)-4-ketobutyric acid is dissolved in 1.2L ethylene dichloride, adds the anhydrous AlCl of 150g
3.This mixture was 60 degree of reacting by heating 4 hours.Reaction solution cool to room temperature, control temperature is no more than 35 degree, adds the hydrochloric acid of 1L3N under stirring in batches.Separatory, then aqueous phase 600mL ethylene dichloride extraction, merges organic phase.Dried over sodium sulfate organic phase, then filtering and concentrating, obtain chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone 168g of off-white color solid 7-, yield 91.3%.H
1NMR（300MHz,CDCl
3）:δ2.91(m,4H),7.24～7.26(m,1H),7.42～7.52(m,2H)。
(3) chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone of 150g7-, 85% hydrazine hydrate 165g, KOH60g once adds in 500mL ethylene glycol.Stir after nitrogen replacement and be warming up to 165 degree and react 4 hours.Reaction mixture is cooled to room temperature, under stirring state, is added by mixture in 4L salt solution, has a large amount of off-white color solid to separate out.Collecting by filtration white solid, dry chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen) the-one 119g of product 7-, productive rate 85%, HPLC detects purity and is greater than 98%, and single contaminant is less than 0.5%.H
1NMR(DMSO-d6):δ9.56(s,1H,NH),6.96～7.36(3H,aromatics),2.67～2.70(t,2H,CH
2),2.06～2.18(m,4H,CH
2CH
2)。
The synthesis of chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of embodiment 29-
(1) 64g4-chloroaniline and 50g Succinic anhydried are dissolved in 300mL ethylene dichloride, then heating reflux reaction 6 hours.Remove ethylene dichloride under reduced pressure after reaction terminates, in resistates, add the hydrochloric acid of the cold 1N of 150mL, stir 10 minutes; Filter to obtain white solid 4-(2-chloroanilino)-4-ketobutyric acid 108g, yield 93.7%.H
1NMR(300MHz,DMSO-d6):δ2.60(m,4H),7.39～7.59(m,4H),10.04(br,1H),12.35(br,1H)。
(2) 100g4-(2-chloroanilino)-4-ketobutyric acid is dissolved in 600mL ethylene dichloride, adds the anhydrous AlCl of 75g
3.This mixture was 60 degree of reacting by heating 4 hours.Reaction solution cool to room temperature, control temperature is no more than 35 degree, adds the hydrochloric acid of 500mL3N under stirring in batches.Separatory, then aqueous phase 300mL ethylene dichloride extraction, merges organic phase.Dried over sodium sulfate organic phase, then filtering and concentrating, obtain chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone 85g of off-white color solid 9-, yield 91.4%.H
1NMR（300MHz,CDCl3）:2.93(m,4H),7.42～7.62(m,3H)。
(3) chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone of 76g9-, 85% hydrazine hydrate 83g, KOH31g once adds in 255mL ethylene glycol.Stir after nitrogen replacement and be warming up to 165 degree and react 4 hours.Reaction mixture is cooled to room temperature, under stirring state, is added by mixture in 2L salt solution, has a large amount of off-white color solid to separate out.Collecting by filtration white solid, dry chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen) the-one 60g of product 9-, productive rate 85%, HPLC detects purity and is greater than 98.5%, and single contaminant is less than 0.5%.H
1NMR(DMSO-d6):δ9.53(s,1H,NH),7.40～7.58(m,3H),2.65～2.69(t,2H,CH
2),2.04～2.16(m,4H,CH
2CH
2)。
Preparation method's yield provided by the invention is high, simple to operate, and total recovery is higher, and product is purified convenient, and cost is lower, is applicable to suitability for industrialized production.
Claims (5)
1.7 or the synthetic method of chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of 9-, comprise the following steps:
A, Ortho-Chloro aniline or p-Chlorobenzoic acid amide and Succinic anhydried react: be dissolved in organic solvent by Ortho-Chloro aniline or p-Chlorobenzoic acid amide and Succinic anhydried, then heating reflux reaction 4 ~ 8 hours, reaction terminates rear removing organic solvent, adds the hydrochloric acid of cold 1N, stir 10 ~ 15 minutes in resistates; Filter out solid, obtain 4-(2 or 4-chloroanilino)-4-ketobutyric acid;
Friedel-Crafts reaction in B, molecule: above-mentioned 4-(2 or 4-chloroanilino)-4-ketobutyric acid is dissolved in ethylene dichloride, adds aluminum trichloride (anhydrous), then 55 ~ 70 DEG C of reactions 4 ~ 6 hours; Then by above-mentioned reaction solution cool to room temperature, control temperature is no more than 35 DEG C, adds the hydrochloric acid of 3N ~ 6N; Separatory retains organic phase again, and then aqueous phase ethylene dichloride extracts, and merges organic phase, organic phase after drying, solids removed by filtration, organic phase is concentrated except desolventizing, obtains 7 or chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone of 9-;
C, Huang Min-lon reduction: 7 or chloro-3,4-dihydro-1 hydrogen-benzo [b] azatropylidene-2, the 5-diketone of 9-, ethylene glycol, hydrazine hydrate and potassium hydroxide react 4 ~ 6 hours at 150 ~ 170 DEG C; Reaction solution is down to room temperature, adds salt solution, filter, obtain 7 or chloro-4,5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one of 9-.
2. according to claim 17 or 9-chloro-4, the synthetic method of 5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one, is characterized in that: the mol ratio of the Ortho-Chloro aniline described in steps A or p-Chlorobenzoic acid amide and Succinic anhydried is 1:0.95 ~ 1.05.
3. according to claim 17 or 9-chloro-4, the synthetic method of 5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one, is characterized in that: the organic solvent described in steps A is any one in ethylene dichloride, tetrahydrofuran (THF) or glycol dimethyl ether.
4. according to claim 17 or 9-chloro-4, the synthetic method of 5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one, is characterized in that: the mol ratio of 4-described in step B (2 or 4-chloroanilino)-4-ketobutyric acid and aluminum trichloride (anhydrous) is 1:1.0 ~ 1.5.
5. according to claim 17 or 9-chloro-4, the synthetic method of 5-dihydro-1 hydrogen-benzo [b] azatropylidene-2 (3 hydrogen)-one, it is characterized in that: 7 described in step C or 9-chloro-3, the mol ratio of 4-dihydro-1 hydrogen-benzo [b] azatropylidene-2,5-diketone, hydrazine hydrate and potassium hydroxide is 1:5.0 ~ 7.0:1.3 ~ 1.8.
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| CN103288709A (en) * | 2013-05-17 | 2013-09-11 | 安徽世华化工有限公司 | Synthesis method of 5-fluorine-indol-2-ketone |
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| CN102174016A (en) * | 2011-03-02 | 2011-09-07 | 宁波人健药业集团有限公司 | Method for preparing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzoazepine-2,5-diketone |
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