CN105037168A - Preparation of S-5-bromo-1-aminoindane by resolution of D-tartaric acid - Google Patents
Preparation of S-5-bromo-1-aminoindane by resolution of D-tartaric acid Download PDFInfo
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- CN105037168A CN105037168A CN201510543952.2A CN201510543952A CN105037168A CN 105037168 A CN105037168 A CN 105037168A CN 201510543952 A CN201510543952 A CN 201510543952A CN 105037168 A CN105037168 A CN 105037168A
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- China
- Prior art keywords
- bromo
- aminoidan
- tartrate
- indone
- solvent
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- 238000002360 preparation method Methods 0.000 title claims description 8
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 title abstract 2
- 229960001270 d- tartaric acid Drugs 0.000 title abstract 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 23
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052759 nickel Inorganic materials 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 229910021529 ammonia Inorganic materials 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 6
- 239000012141 concentrate Substances 0.000 claims description 5
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 230000007423 decrease Effects 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 1
- 239000012043 crude product Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 abstract description 2
- IEUKCNPRRGOGDG-UHFFFAOYSA-N 5-bromo-2,3-dihydro-1h-inden-1-amine Chemical compound BrC1=CC=C2C(N)CCC2=C1 IEUKCNPRRGOGDG-UHFFFAOYSA-N 0.000 abstract 3
- KSONICAHAPRCMV-UHFFFAOYSA-N 5-bromo-2,3-dihydroinden-1-one Chemical compound BrC1=CC=C2C(=O)CCC2=C1 KSONICAHAPRCMV-UHFFFAOYSA-N 0.000 abstract 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000005194 fractionation 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 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Indole Compounds (AREA)
Abstract
The invention discloses a method for preparing S-5-bromo-1-aminoindane by taking 5-bromo-1-indanone as a starting material. The specific operation is as follows: in a high-pressure kettle, taking alcohol as a solvent, 5-bromo-1-indanone as a raw material, a nickel/diatomite supported catalyst KT-02 as a hydrogenation catalyst, liquid ammonia as an ammoniation reagent, and introducing hydrogen for hydrogenation reduction to obtain 5-bromo-1-aminoindane; the obtained crude product of 5-bromo-1-aminoindan can be subjected to the next reaction without purification; (2) in an alcohol solvent, a resolving agent D-tartaric acid reacts with 5-bromo-1-aminoindan to obtain D-tartrate of S-5-bromo-1-aminoindan; recrystallizing and purifying salt with alcohol solution; (3) and alkalifying the purified salt with alkali to obtain the product S-5-bromo-1-aminoindane. The technical method provided by the invention has the characteristics of simple operation, high splitting efficiency, low production cost and the like, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of optical homochiral amine, particularly relate to a kind of with 5-bromo-1-indone for the method for the bromo-1-aminoidan of optical purity S-5-prepared by raw material.
Background technology
S-5-bromo-1-aminoidan is the very important chiral medicinal intermediate of a class.In existing S-5-bromo-1-aminoidan relevant report, then rarely has report about how preparing the bromo-1-aminoidan of optical purity S-5-.How obtaining a kind of efficient, convenient method preparing S-5-bromo-1-aminoidan is problem to be solved by this invention.
Summary of the invention
The object of this invention is to provide the method that the low and simple fractionation of a kind of cost obtains the bromo-1-aminoidan of optical purity S-5-.The present invention be a kind of with 5-bromo-1-indone for the bromo-1-aminoidan of S-5-prepared by raw material, concrete operations are as follows: in (1) autoclave, with methyl alcohol or ethanol for solvent, add the bromo-1-indone of raw material 5-successively by a certain percentage, hydrogenation catalyst nickel/kieselguhr supported catalyst KT-02, sealing autoclave, nitrogen replacement goes out in still after air, then uses hydrogen exchange nitrogen; After having replaced, pass into a certain amount of liquefied ammonia as aminating agent; Finally pass into hydrogen pressure, and intensification is reacted; After certain hour, no longer decline to hydrogen pressure, stopped reaction; After reaction terminates, with the hydrogen in nitrogen eliminating system, remaining ammonia; Filtration of catalyst, concentrates to obtain the bromo-1-aminoidan of 5-; (2) add in alcoholic solvent and walk the bromo-1-aminoidan of gained 5-, and a certain amount of D-tartrate, stir, heat up, under reflux conditions, react certain hour, terminate rear cooling, D-tartrate that crystallization, suction filtration obtain the bromo-1-aminoidan of S-5-; Gained salt alcoholic solvent recrystallization carries out purifying; (3) salt after purifying is dissolved in a certain amount of water, adds alkali lye and regulates pH value; The bromo-1-aminoidan of S-5-is operated to obtain again through organic solvent extraction, drying, concentrate etc.
When preparing the bromo-1-aminoidan of 5-according to hydro-reduction in described the present invention, hydrogenation catalyst used therein is nickel/kieselguhr supported catalyst KT-02, add that quality is the bromo-1-indone of 5-5% ~ 20%; When hydro-reduction prepares 5-bromo-1-aminoidan, aminating agent used is liquefied ammonia, and the equivalence ratio of liquefied ammonia and the bromo-1-indone of 5-is 5:1 ~ 10:1; When hydro-reduction prepares 5-bromo-1-aminoidan, reactive hydrogen atmospheric pressure is 1.0 ~ 3.0MPa; When hydro-reduction prepares 5-bromo-1-aminoidan, temperature of reaction is 60 ~ 90 DEG C; During fractionation 5-bromo-1-aminoidan, resolving agent used is D-tartrate; The equivalence ratio of D-tartrate and the bromo-1-aminoidan of 5-is 1:1 ~ 3:1; When fractionation and recrystallization reaction, solvent for use alcohol is methyl alcohol or ethanol.
Technique of the present invention possesses following advantage: (1) 5-bromo-1-aminoidan preparation process is simple, convenient.(2) in split process, chiral resolving agent fractionation efficiency is high, stable chemical nature.(3) processing condition are gentle, are suitable for suitability for industrialized production.(4) products obtained therefrom S-5-bromo-1-aminoidan purity is greater than 99%, ee value and is greater than 99%.The present invention be the fractionation preparation of optical purity S-5-bromo-1-aminoidan provide referentially to save time, economic, preparation method efficiently.
Specific implementation method:
(1) preparation of the bromo-1-aminoidan of 5-
In 1000ml autoclave, add 600ml methyl alcohol successively, 105g(0.5mol) the bromo-1-indone of 5-, 10g catalyzer KT-02; Sealing autoclave, with hydrogen by after air displacement secondary in reactor, liquefied ammonia 51g(3.0mol is passed into) in still, liquefied ammonia adds complete, and passing into hydrogen to pressure is 2.0MPa, opens and stirs, and be warming up to 70 DEG C and react, when hydrogen pressure no longer reduces, stopped reaction, by reacting liquid filtering, concentrates to obtain the bromo-1-aminoidan of 5-.
(2) the bromo-1-aminoidan of 5-splits
In 1000ml round-bottomed flask, add 18.0G(0.12mol) D-tartrate, 400ml methyl alcohol, magnetic agitation, adds 21.1G(0.1mol at 55 DEG C) the bromo-1-aminoidan of 5-, back flow reaction 1.5h.Naturally cooling, is chilled to room temperature, and separate out precipitation, suction filtration obtains the D-tartrate crude product 15.1g of the bromo-1-aminoidan of S-5-.Use 140ml recrystallizing methanol, obtain the D-tartrate that 13.9g refines the bromo-1-aminoidan of S-5-, yield is 40.5%.
(3) the bromo-1-aminoidan of S-5-is prepared
The D-tartrate 13.9g of the bromo-1-aminoidan of upper step gained S-5-is dissolved in 200ml water, drip ammonia soln and regulate pH value to 13,3 times are extracted with methylene dichloride (100ml, 50ml, 50ml), dichloromethane layer merges, with water (50ml), saturated brine (50ml) respectively washing once, anhydrous sodium sulfate drying, filtration, concentratedly to obtain S-5-bromo-1-aminoidan 7.8g, yield is 37.0%, ee value is 99.5%.
Claims (7)
1. disclosed by the invention be a kind of with 5-bromo-1-indone for starting raw material prepares the method for the bromo-1-aminoidan of optical purity S-5-, concrete steps operation is as follows: in (1) autoclave, with methyl alcohol or ethanol for solvent, add the bromo-1-indone of raw material 5-successively by a certain percentage, hydrogenation catalyst nickel/kieselguhr supported catalyst KT-02, sealing autoclave, nitrogen replacement goes out in still after air, then uses hydrogen exchange nitrogen; After having replaced, pass into a certain amount of liquefied ammonia as aminating agent; Finally pass into hydrogen pressure, and intensification is reacted; After certain hour, no longer decline to hydrogen pressure, stopped reaction; After reaction terminates, with the hydrogen in nitrogen eliminating system, remaining ammonia; Filtration of catalyst, concentrates to obtain the bromo-1-aminoidan of 5-; (2) add in alcoholic solvent and walk the bromo-1-aminoidan of gained 5-, and a certain amount of D-tartrate, stir, heat up, under reflux conditions, react certain hour, terminate rear cooling, D-tartrate that crystallization, suction filtration obtain the bromo-1-aminoidan of S-5-; Gained salt alcoholic solvent recrystallization carries out purifying; (3) salt after purifying is dissolved in a certain amount of water, adds alkali lye and regulates pH value; The bromo-1-aminoidan of S-5-is operated to obtain again through organic solvent extraction, drying, concentrate etc.; Its reaction equation is as follows:
2. the preparation method of the bromo-1-aminoidan of a kind of S-5-according to claim 1, it is characterized in that: when hydro-reduction prepares 5-bromo-1-aminoidan, hydrogenation catalyst used therein is nickel/kieselguhr supported catalyst KT-02, add that quality is the bromo-1-indone of 5-5% ~ 20%.
3. a kind of method preparing the bromo-1-aminoidan of S-5-according to claim 1, is characterized in that: when hydro-reduction prepares 5-bromo-1-aminoidan, aminating agent used is liquefied ammonia, and the equivalence ratio of liquefied ammonia and the bromo-1-indone of 5-is 5:1 ~ 10:1.
4. a kind of method preparing the bromo-1-aminoidan of S-5-according to claim 1, is characterized in that: when hydro-reduction prepares 5-bromo-1-aminoidan, reactive hydrogen atmospheric pressure is 1.0 ~ 3.0MPa.
5. a kind of method preparing the bromo-1-aminoidan of S-5-according to claim 1, is characterized in that: when hydro-reduction prepares 5-bromo-1-aminoidan, temperature of reaction is 60 ~ 90 DEG C.
6. a kind of method preparing the bromo-1-aminoidan of S-5-according to claim 1, is characterized in that: when splitting 5-bromo-1-aminoidan, resolving agent used is D-tartrate; The equivalence ratio of D-tartrate and the bromo-1-aminoidan of 5-is 1:1 ~ 3:1.
7. a kind of method preparing the bromo-1-aminoidan of S-5-according to claim 1, is characterized in that: split and recrystallization reaction time solvent for use alcohol be methyl alcohol or ethanol.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510543952.2A CN105037168A (en) | 2015-08-31 | 2015-08-31 | Preparation of S-5-bromo-1-aminoindane by resolution of D-tartaric acid |
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| CN201510543952.2A CN105037168A (en) | 2015-08-31 | 2015-08-31 | Preparation of S-5-bromo-1-aminoindane by resolution of D-tartaric acid |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008063671A2 (en) * | 2006-11-20 | 2008-05-29 | Alantos Pharmaceuticals Holding, Inc. | Heterobicyclic metalloprotease inhibitors |
| CN101730683A (en) * | 2007-07-05 | 2010-06-09 | 埃斯蒂文博士实验室股份有限公司 | Indane-amine derivatives, their preparation and use as medicaments |
| WO2012116752A1 (en) * | 2011-03-03 | 2012-09-07 | Synthon Bv | Process of resolution of 1-aminoindan |
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- 2015-08-31 CN CN201510543952.2A patent/CN105037168A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008063671A2 (en) * | 2006-11-20 | 2008-05-29 | Alantos Pharmaceuticals Holding, Inc. | Heterobicyclic metalloprotease inhibitors |
| CN101730683A (en) * | 2007-07-05 | 2010-06-09 | 埃斯蒂文博士实验室股份有限公司 | Indane-amine derivatives, their preparation and use as medicaments |
| WO2012116752A1 (en) * | 2011-03-03 | 2012-09-07 | Synthon Bv | Process of resolution of 1-aminoindan |
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Application publication date: 20151111 |