CN103539677B - Preparation method of 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride - Google Patents
Preparation method of 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims description 5
- ZOVIYWYFBOQKIA-UHFFFAOYSA-N 5,6-diethyl-2,3-dihydro-1h-inden-2-amine;hydrochloride Chemical compound Cl.C1=C(CC)C(CC)=CC2=C1CC(N)C2 ZOVIYWYFBOQKIA-UHFFFAOYSA-N 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims abstract description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 11
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 10
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000000605 extraction Methods 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- 239000000376 reactant Substances 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 claims description 5
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 5
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012346 acetyl chloride Substances 0.000 claims description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 238000005583 trifluoroacetylation reaction Methods 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 238000006386 neutralization reaction Methods 0.000 claims description 2
- 238000006146 oximation reaction Methods 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 11
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- QZZUEBNBZAPZLX-QFIPXVFZSA-N indacaterol Chemical compound N1C(=O)C=CC2=C1C(O)=CC=C2[C@@H](O)CNC1CC(C=C(C(=C2)CC)CC)=C2C1 QZZUEBNBZAPZLX-QFIPXVFZSA-N 0.000 abstract description 5
- 229960004078 indacaterol Drugs 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 229910052763 palladium Inorganic materials 0.000 abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 abstract 2
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 abstract 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 238000006640 acetylation reaction Methods 0.000 abstract 1
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract 1
- 239000001257 hydrogen Substances 0.000 abstract 1
- 230000007062 hydrolysis Effects 0.000 abstract 1
- 238000006460 hydrolysis reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000020477 pH reduction Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 abstract 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 abstract 1
- 230000005311 nuclear magnetism Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- -1 palladium hydrogenated carbon Chemical class 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 206010006440 Bronchial obstruction Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010061876 Obstruction Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- FBSMERQALIEGJT-UHFFFAOYSA-N chlorpromazine hydrochloride Chemical compound [H+].[Cl-].C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 FBSMERQALIEGJT-UHFFFAOYSA-N 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of synthesis of a medical immediate, and particularly relates to a synthesis method of a key intermediate 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride of indacaterol. The method comprises the following steps: by taking ethylbenzene as a raw material, preparing a compound I by propionyl chloride; preparing a compound II from the compound I by cyclization reaction; preparing a compound III by reaction of the compound II and butyl nitrite; preparing a compound IV from the compound III by palladium hydrogen reduction; finally preparing a compound V from the compound IV under protection of trifluoroacetyl; preparing a compound VI from the compound V by amino acetylation reaction; preparing a compound VII from the compound VI by reduction; carrying out deprotection, hydrolysis and acidification on the compound VII, so as to obtain the final product compound VIII, namely the 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride. The method disclosed by the invention is simple and convenient to operate, reasonable in reaction flow, low in cost, good in product quality, free of pollution to environment, and applicable to industrial production; the content is greater than 99%.
Description
Technical field
The present invention relates to the synthesis technical field of medicine intermediate, be specifically related to a kind of synthetic method of key intermediate 5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate of QAB-149.
Background technology
QAB-149 is that a kind of Novel ultralong developed by Novartis Co., Ltd of Switzerland imitates beta 2 receptor agonist.This medicine obtains U.S. FDA approval listing on July 1st, 2011.This medicine is used for there is chronic bronchial obstruction disease (COPD) airflow obstruction patient, comprises chronic bronchitis and/or emophysematous treatment.5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate is as the intermediate of QAB-149 most critical, and therefore its market outlook and economic benefit have very large potentiality.
5; 6-diethyl-2; 3-dihydro-1H-indenes-2-amine hydrochlorate at document (as Organic Process Research & Development 2006; 10; 135141) synthetic method reported is mainly with 2; 3-dihydro-1H-indenes-2-amine is raw material, protects amino through trifluoroacetylation, then through twice chloroacetylation and twice palladium hydrogenated carbon reduction finally goes protection salify to obtain finalization compound again.And raw material 2,3-dihydro-1H-indenes-2-amine is rare on market and expensive commodity, there is a definite limitation to the suitability for industrialized production of 5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate.
Summary of the invention
For the deficiencies in the prior art, the object of the present invention is to provide a kind of novel synthesis of compound 5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate.
Technical conceive of the present invention is: with commercial be easy to get and the ethylbenzene of cheapness instead of bibliographical information with 2,3-dihydro-1H-indenes-2-amine as starting raw material, propionating through chlorine; cyclisation; oximate, palladium hydrogenated carbon reduces, amido protecting; acetylize; reduction, goes protection and salify thus obtain the finished product, i.e. the intermediate 5 of QAB-149; 6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate.
The technical scheme realizing the object of the invention is as follows:
A kind of preparation method of 5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate, its step is as follows:
(1) ethylbenzene take methylene dichloride as solvent, and aluminum chloride is promotor, and through 3 chlorpromazine chloride acidylates under-5-25 ° of C, reactant is through extracting dry chemical compounds I, and wherein ethylbenzene, 3-chlorpromazine chloride, aluminum chloride consumption mol ratio are 1:1-2:1-2;
(2) chemical compounds I is dissolved in the vitriol oil under-5-5 ° of C, reheats 90-100oC and carries out cyclization, and then extract drying and obtain compound ii, wherein the consumption mass ratio of chemical compounds I and the vitriol oil is 1:4-6;
(3) compound ii take concentrated hydrochloric acid as promotor, methyl alcohol is solvent, under 40 DEG C of conditions, obtain compound III through nitrous acid straight butyl oximation reaction, reactant crystallization, drying, the consumption mol ratio of compound ii, nitrous acid straight butyl, concentrated hydrochloric acid (HCl wherein) three is 1:1-1.5:1-2;
(4) compound III take glacial acetic acid as solvent, and the vitriol oil is that promotor obtains compounds Ⅳ through under high pressure hydro-reduction, reactant extraction, the drying of palladium carbon, and the mass ratio of compound III, palladium charcoal, vitriol oil three is 1:0.1-0.3:1-3;
(5) compounds Ⅳ is solvent with ethyl acetate, in nitrogen, under 0-7 ° of C through Trifluoroacetic Acid Ethyl Ester trifluoroacetylation protection, room temperature reaction, cross post, dry compound V, the consumption mol ratio of compounds Ⅳ and Trifluoroacetic Acid Ethyl Ester is 1:1-2;
(6) compound V take methylene dichloride as solvent, aluminum chloride is promotor, in nitrogen, obtain compound VI under 0-5 DEG C of condition through Acetyl Chloride 98Min. acidylate, extraction, drying, recrystallization, excessively post, the consumption mol ratio of compound V, Acetyl Chloride 98Min., aluminum chloride three is 1:2-4:2-4;
(7) compound VI take trifluoroacetic acid as solvent, and through the reduction of triethyl silicane room temperature, neutralization, extraction, crystallization, dry compound VII, compound VI is 1:2-5 with the consumption mol ratio of triethyl silicane;
(8) compound VII is with after dissolve with methanol, add sodium hydroxide solution to be at room temperature hydrolyzed, through extraction, in ether solvent, logical hydrogen chloride gas is acidified after drying, after completion of the reaction suction filtration, dry compound VIII, and compound VII is 1:8-12 with the consumption mol ratio of sodium hydroxide.Reaction principle is as follows:
Compared with prior art, the advantage of technical solution of the present invention and beneficial effect are:
1, the ethylbenzene be easy to get with business instead of bibliographical information with 2,3-dihydro-1H-indenes-2-amine as starting raw material, industrializing implementation is more prone to.
2, because material ethylbenzene is cheap, the production cost of the finished product is about only about 50% of existing method cost.
Embodiment
Applicant will further illustrate method of the present invention in conjunction with specific embodiments below, but following content should not be construed as the restriction to claims of the present invention request protection domain.
Embodiment 1:
A kind of preparation method of 5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate, its step is as follows:
(1) synthesis of chemical compounds I
Aluminum chloride 780g and methylene dichloride 8L is dropped in 10L there-necked flask, be cooled to-1-1 DEG C, drip 600g3-chlorpromazine chloride, drip off rear reaction 30min, drip ethylbenzene 500g again, after dropwising, rise to room temperature (20-25 DEG C) reaction 8h, then reactant is poured into extraction in 10L1M hydrochloric acid frozen water (the frozen water mixed solution of hydrochloric acid) and go out, dichloromethane extraction, saturated sodium bicarbonate washing once, is washed once, anhydrous sodium sulfate drying, be spin-dried for, then freezing and crystallizing, dry 847g solid, fusing point 63-64 DEG C, product is confirmed through nuclear-magnetism, yield 90%.
(2) synthesis of compound ii
98% vitriol oil 1.5L drops in 3L there-necked flask, cryosel bath is cooled to-1 DEG C-1 DEG C, and slowly (within 10 minutes, adding) adds chemical compounds I 500g, goes to oil bath after adding, be warming up to 90 DEG C, reaction 2h, then reactant is poured in trash ice, extraction into ethyl acetate, saturated sodium bicarbonate washing once, once, anhydrous sodium sulfate drying, is spin-dried for obtain brown oil solid 347g in water washing.Fusing point 42-44 DEG C, yield 85%, product is confirmed through nuclear-magnetism.
(3) synthesis of compound III
Compound ii 232g is added in there-necked flask, methyl alcohol 1.5L, control temperature 23-28 DEG C, drips nitrous acid straight butyl 164g, drips off rear reaction 30min, then 36wt% concentrated hydrochloric acid 145mL is dripped, under 40 DEG C of conditions, react 3h after dripping off, screw out partial solvent to about 400mL, refrigerator freezing crystallization, suction filtration, obtains yellow solid 191g.Fusing point 177-178 DEG C, yield 70%, product is confirmed through nuclear-magnetism.
(4) synthesis of compounds Ⅳ
By 60g compound III, 15g10% palladium carbon (10%Pd/C), 80mL98% sulfuric acid, 0.8L glacial acetic acid adds hydrogenation in autoclave and, to 12bar, reacts 24h, then filter, screw out part glacial acetic acid to about 200mL, regulate pH to 11, through dichloromethane extraction with sodium hydroxide solution, anhydrous sodium sulfate drying, is spin-dried for obtain 39g oily matter.Yield 78%, product is confirmed through nuclear-magnetism.
(5) synthesis of compound V
Compounds Ⅳ 31g is added in there-necked flask, ethyl acetate 200mL, logical nitrogen, ice bath is cooled to 0-5 DEG C, drips Trifluoroacetic Acid Ethyl Ester 33g, after dripping off, 3-7 DEG C of reaction 2h, then room temperature (20-25 DEG C) is reacted 12 hours, is spin-dried for, dissolve with 100mL methylene dichloride, after filtered through silica gel, be spin-dried for obtain 44g product.Fusing point 112-114 DEG C, product is confirmed through nuclear-magnetism, yield 90%.
(6) synthesis of compound VI
In there-necked flask, add aluminum chloride 58g, methylene dichloride 400mL, cryosel bath temperature control is to 0-5 DEG C, and logical nitrogen, drips Acetyl Chloride 98Min. 41g, drip off rear reaction 30min, then drips the dichloromethane solution 100mL containing 45g compound V, drips off rear reaction 1h.Reactant is poured in 1M hydrochloric acid frozen water to extract and is gone out, through dichloromethane extraction, saturated sodium bicarbonate solution washing once, once, anhydrous sodium sulfate drying, is spin-dried for obtain 51g solid in washing, be that the methylene dichloride of 1:3 and normal hexane mixed solvent recrystallization obtain 26g pure compound VI by volume ratio, mother liquor is spin-dried for post and is separated to obtain 23g compound VI, and product is confirmed through nuclear-magnetism, productive rate 87%.
(7) synthesis of compound VII
With 320mL trifluoroacetic acid, 71g compound VI is dissolved, slowly drip triethyl silicane 160mL, under within 10 minutes, dripping off rear room temperature (20-25 DEG C), react 12h.Pour extraction in frozen water into go out, be adjusted to neutrality, extraction into ethyl acetate, add 100mL sherwood oil, freezing and crystallizing after being spin-dried for solvent with the sodium hydroxide solution of 4M, suction filtration is dry obtains 65g compound VII, and fusing point 159.0-159.5 DEG C, productive rate 96%, product is confirmed through nuclear-magnetism.
(8) synthesis of compound VIII
50g compound VII 250mL dissolve with methanol, adds 250mL5M sodium hydroxide solution, room temperature (20-25 DEG C) reaction 8h, then add water 500mL, and dichloromethane extraction, is spin-dried for solvent, add 600mL ether dissolution, then pass into hydrogen chloride gas, until TLC display reaction is complete, stop ventilation, suction filtration, is drying to obtain compound VIII 5,6-diethyl-2,3-dihydro-1H-indenes-2-amine hydrochlorate 33g, productive rate 100%, purity 99.1%, fusing point more than 250 DEG C.Product is confirmed through nuclear-magnetism.
Claims (1)
1. the preparation method of diethyl-2, a 3-dihydro-1H-indenes-2-amine hydrochlorate, its step is as follows:
(1) ethylbenzene take methylene dichloride as solvent, and aluminum chloride is promotor, and through 3-chlorpromazine chloride acidylate under-5-25oC, reactant is through extracting dry chemical compounds I;
(2) chemical compounds I is dissolved in the vitriol oil under-5-5oC, reheats 90-100
oc carries out cyclization, then extracts drying and obtains compound ii;
(3) compound ii take concentrated hydrochloric acid as promotor, and methyl alcohol is solvent, under 40 DEG C of conditions, obtains compound III through nitrous acid straight butyl oximation reaction, reactant crystallization, drying;
(4) compound III take glacial acetic acid as solvent, and the vitriol oil is that promotor obtains compounds Ⅳ through under high pressure hydro-reduction, reactant extraction, the drying of palladium charcoal;
(5) compounds Ⅳ is solvent with ethyl acetate, in nitrogen, under 0-7oC through Trifluoroacetic Acid Ethyl Ester trifluoroacetylation protection, room temperature reaction, cross post, dry compound V;
(6) compound V take methylene dichloride as solvent, and aluminum chloride is promotor, in nitrogen, obtain compound VI under 0-5 DEG C of condition through Acetyl Chloride 98Min. acidylate, extraction, drying, recrystallization, excessively post;
(7) compound VI take trifluoroacetic acid as solvent, through the reduction of triethyl silicane room temperature, neutralization, extraction, crystallization, dry compound VII;
(8) compound VII is with after dissolve with methanol, adds sodium hydroxide solution and is at room temperature hydrolyzed, and through extraction, in ether solvent, logical hydrogen chloride gas is acidified after drying, after completion of the reaction suction filtration, dry product compound VIII;
In described step (1), ethylbenzene, 3-chlorpromazine chloride, aluminum chloride consumption mol ratio are 1:1-2:1-2;
In described step (2), the consumption mass ratio of chemical compounds I and the vitriol oil is 1:4-6, and vitriol oil concentration is 98wt%;
In described step (3), the consumption mol ratio of compound ii, nitrous acid straight butyl, concentrated hydrochloric acid three is 1:1-1.5:1-2, and the concentration of described concentrated hydrochloric acid is 36wt%;
In described step (4), the mass ratio of compound III, palladium charcoal, vitriol oil three is 1:0.1-0.3:1-3, and hydrogenation pressure is 10-12bar, and this step reaction makes solvent with glacial acetic acid, and palladium charcoal is 10% palladium charcoal, and vitriol oil concentration is 98wt%;
In described step (5), the consumption mol ratio of compounds Ⅳ and Trifluoroacetic Acid Ethyl Ester is 1:1-2;
In described step (6), the consumption mol ratio of compound V, Acetyl Chloride 98Min., aluminum chloride three is 1:2-4:2-4;
In described step (7), compound VI is 1:2-5 with the consumption mol ratio of triethyl silicane, and this step reaction makes solvent with trifluoroacetic acid;
In described step (8), compound VII is 1:8-12 with the consumption mol ratio of sodium hydroxide.
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| CN201210243549.4A CN103539677B (en) | 2012-07-16 | 2012-07-16 | Preparation method of 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride |
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| CN201210243549.4A CN103539677B (en) | 2012-07-16 | 2012-07-16 | Preparation method of 5,6-diethyl-2,3-dihydro-1H-indene-2-amine hydrochloride |
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| CN103539677B true CN103539677B (en) | 2015-04-22 |
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| CN106831445B (en) * | 2016-11-22 | 2019-01-22 | 斯芬克司药物研发（天津）股份有限公司 | A kind of preparation method of indenyl amine compounds |
| CN109369417B (en) * | 2018-10-19 | 2021-07-06 | 诚达药业股份有限公司 | Preparation method of 2-aminoindane derivative |
| CN113735737B (en) * | 2021-08-20 | 2022-10-04 | 山东阳谷华泰化工股份有限公司 | Preparation method of p-benzoquinone dioxime |
| CN114031520B (en) * | 2021-11-02 | 2025-08-19 | 浙大宁波理工学院 | 2- (2- (5-Acetamido-2, 4-dichlorophenyl) hydrazono) propionic acid compound and synthesis method thereof |
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| CN1353692A (en) * | 1999-06-04 | 2002-06-12 | 诺瓦提斯公司 | Betz 2-adrenoceptor agonists |
| CN1639111A (en) * | 2002-03-08 | 2005-07-13 | 诺瓦提斯公司 | Process for preparing 2-aminoindan derivatives |
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