CN105085279A - Preparation of R-5-chloro-1-aminoindane - Google Patents
Preparation of R-5-chloro-1-aminoindane Download PDFInfo
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- CN105085279A CN105085279A CN201510529757.4A CN201510529757A CN105085279A CN 105085279 A CN105085279 A CN 105085279A CN 201510529757 A CN201510529757 A CN 201510529757A CN 105085279 A CN105085279 A CN 105085279A
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- chloro
- aminoidan
- resolving agent
- method preparing
- solvent
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- CCNOGOGUHOMLMI-SECBINFHSA-N (1r)-5-chloro-2,3-dihydro-1h-inden-1-amine Chemical compound ClC1=CC=C2[C@H](N)CCC2=C1 CCNOGOGUHOMLMI-SECBINFHSA-N 0.000 title abstract 5
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 13
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 230000020477 pH reduction Effects 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 229960002510 mandelic acid Drugs 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000012141 concentrate Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- IWYDHOAUDWTVEP-ZETCQYMHSA-N (S)-mandelic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-ZETCQYMHSA-N 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- -1 5-chloro-1-indanone oxime azanol Chemical compound 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 229960004249 sodium acetate Drugs 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000004904 shortening Methods 0.000 claims description 2
- CCNOGOGUHOMLMI-UHFFFAOYSA-N 5-chloro-2,3-dihydro-1h-inden-1-amine Chemical compound ClC1=CC=C2C(N)CCC2=C1 CCNOGOGUHOMLMI-UHFFFAOYSA-N 0.000 abstract 2
- MEDSHTHCZIOVPU-UHFFFAOYSA-N 5-chloro-2,3-dihydroinden-1-one Chemical compound ClC1=CC=C2C(=O)CCC2=C1 MEDSHTHCZIOVPU-UHFFFAOYSA-N 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000005755 formation reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000007788 liquid Substances 0.000 abstract 1
- 150000002923 oximes Chemical class 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000005194 fractionation Methods 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- UQTIJEKCRQCDEK-UHFFFAOYSA-N n-(5-chloro-2,3-dihydroinden-1-ylidene)hydroxylamine Chemical compound ClC1=CC=C2C(=NO)CCC2=C1 UQTIJEKCRQCDEK-UHFFFAOYSA-N 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 230000003113 alkalizing effect Effects 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of R-5-chloro-1-aminoindane. The method takes 5-chloro-1-indanone as a starting material, and obtains 5-chloro-1-aminoindane through oxime formation and hydrogenation reaction; resolving 5-chloro-1-aminoindan by using a chiral resolving agent to obtain an enantiomer salt of R-5-chloro-1-aminoindan, recrystallizing the salt, and performing alkalization treatment by using alkali liquor to obtain R-5-chloro-1-aminoindan, wherein the ee value of the obtained R-5-chloro-1-aminoindan is more than 99%; after all the residual liquids containing the resolving agent components are combined, the resolving agent can be recovered through acidification treatment. The technical method provided by the invention is simple to operate, high in resolution efficiency, easy to recycle the resolving agent and the resolving solvent, economic and environment-friendly, and suitable for industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of optical homochiral compound, particularly relate to a kind of with 5-chloro-1-indone for starting raw material prepares the method for the chloro-1-aminoidan of R-5-.
Background technology
R-5-chloro-1-aminoidan is the very important chiral medicinal intermediate of a class.In existing 5-chloro-1-aminoidan relevant report, then rarely has report about how preparing the chloro-1-aminoidan of optical purity R-5-.How obtaining a kind of efficient, convenient method preparing R-5-chloro-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 chloro-1-aminoidan of optical purity R-5-.The present invention be a kind of with the chloro-1-indone of 5-for starting raw material, in alcoholic solvent, generate ketoxime with azanol and alkali reaction, ketoxime obtains the chloro-1-aminoidan of 5-through hydrogenation catalyst shortening; Upper step gained 5-chloro-1-aminoidan and a certain amount of chiral selectors L-amygdalic acid react in suitable alcoholic solution, cooling, crystallization, suction filtration obtain the L-mandelate of the chloro-1-aminoidan of R-5-, after salt recrystallization purifying, be dissolved in the water, operate to obtain the chloro-1-aminoidan of R-5-through alkalization, extraction, drying, concentrate etc., and the ee value of the chloro-1-aminoidan of gained R-5-is greater than 99%; Raffinate containing L-amygdalic acid composition used merges together, operates recyclable L-amygdalic acid through acidifying, extraction, drying, concentrate etc.
Be oxammonium hydrochloride according to described preparation 5-chloro-1-indanone oxime azanol used, alkali used is sodium-acetate, and reaction solvent for use is methyl alcohol or ethanol; The hydrogenation catalyst that ketoxime hydrogenating reduction prepares 5-chloro-1-aminoidan used is Raney's nickel, and it drops into the 5%-20% that quality is 5-chloro-1-indone quality; Splitting R-5-chloro-1-aminoidan resolving agent used is L-amygdalic acid, and the molar ratio of raw material and resolving agent is 1:1.0 ~ 2.0; The solvent that fractionation and recrystallization react used is methyl alcohol or ethanol, and the mass ratio that feeds intake of raw material and solvent is 10 ~ 30; Salinization process alkali used is sodium hydroxide solution or ammonia soln; When reclaiming resolving agent, acidification acid used is hydrochloric acid or sulphuric acid soln.
Technique of the present invention possesses following advantage: (1) hydrogenation catalyst is cheap and easy to get, hydrogenation technique environmental protection.(2) chiral resolving agent fractionation efficiency is high, stable chemical nature, and easily separated recovery uses.(2) processing condition are gentle, are suitable for suitability for industrialized production.(3) products obtained therefrom R-5-chloro-1-aminoidan purity is greater than 99%, ee value and is greater than 99%.(4) the equal recoverable of the organic solution used, uses without special, toxic reagent.The present invention be the fractionation preparation of optical purity R-5-chloro-1-aminoidan provide referentially to save time, economic, preparation method efficiently.
Specific implementation method:
Embodiment 1
(1) preparation of the chloro-1-indanone oxime of 5-
In 1000ml round-bottomed flask, add 600ml methyl alcohol, 166.6g(1.0mol) the chloro-1-indone of 5-, 70g(1.0mol) oxammonium hydrochloride, 98.4g(1.2mol) sodium-acetate, back flow reaction 2h, some plate detects the chloro-1-indone of 5-and disappears.After cooling, under stirring, in system, add 4000ml water, separate out a large amount of white solid, filter, dry 5-chloro-1-indanone oxime 168.7g, yield is 93.2%.
(2) the chloro-1-aminoidan preparation of 5-
In 2000ml autoclave, add 1200ml methyl alcohol, 168.7g5-chloro-1-indanone oxime, 17g Raney's nickel, 300ml ammoniacal liquor, after autoclave sealing, displaced air, pass into hydrogen to pressure 1.5MPa, at 65 DEG C, react 5h, 5-chloro-1-indanone oxime is converted into the chloro-1-aminoidan of 5-, filters, concentrates to obtain the chloro-1-aminoidan of 5-.
(3) the chloro-1-aminoidan of 5-splits
In 1000ml round-bottomed flask, add 22.8G(0.15mol) L-amygdalic acid, 400ml methyl alcohol, magnetic agitation, drips 16.7G(0.1mol at 55 DEG C) the chloro-1-aminoidan of 5-, back flow reaction 1.5h.Naturally cooling, is chilled to room temperature, separates out white precipitate, and suction filtration obtains white and product 13.8g.Use 120ml recrystallizing methanol, obtain the L-mandelate that 12.3g refines the chloro-1-aminoidan of R-5-, yield is 40.9%.
(2) the chloro-1-aminoidan of R-5-is prepared
The L-mandelate 12.3g of the chloro-1-aminoidan of upper step gained R-5-is dissolved in 200ml water, drip 40% sodium hydroxide solution and regulate pH value to 12,3 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 R-5-chloro-1-aminoidan 6.4g, yield is 38.3%, ee value is 99.2%.
(3) resolving agent L-amygdalic acid reclaims
Split and steam except methyl alcohol with recrystallization mother liquor.After cooling, by alkalizing in the mother liquor after concentrated and step 2, remaining aqueous layer afterwards concentrates in together, sulphuric acid soln is used to regulate pH value to 3, with methylene dichloride (150ml, 100ml, 50ml) extract 3 times, methylene dichloride merges, and with water (50ml), saturated brine (50ml) respectively washs once, anhydrous sodium sulfate drying, filtration, concentrated obtaining L-amygdalic acid 20.8, yield is 91.2%.
Embodiment 2
(1) preparation of the chloro-1-indanone oxime of 5-
In 1000ml round-bottomed flask, add 500ml methyl alcohol, 166.6g(1.0mol) the chloro-1-indone of 5-, 83.8g(1.2mol) oxammonium hydrochloride, 123g(1.5mol) sodium-acetate, back flow reaction 3h, some plate detects the chloro-1-indone of 5-and disappears.After cooling, under stirring, in system, add 5000ml water, separate out a large amount of white solid, filter, dry 5-chloro-1-indanone oxime 170.1g, yield is 94.0%.
(4) the chloro-1-aminoidan preparation of 5-
In 2000ml autoclave, add 1000ml methyl alcohol, 170.1g5-chloro-1-indanone oxime, 25g Raney's nickel, 150ml ammoniacal liquor, after autoclave sealing, displaced air, pass into hydrogen to pressure 2.0MPa, at 70 DEG C, react 3h, 5-chloro-1-indanone oxime is converted into the chloro-1-aminoidan of 5-, filters, concentrates to obtain the chloro-1-aminoidan of 5-.
The chloro-1-aminoidan of 5-splits
In 1000ml round-bottomed flask, add 18.2G(0.12mol) L-amygdalic acid, 300ml ethanol, magnetic agitation, drips 16.7G(0.1mol at 50 DEG C) the chloro-1-aminoidan of 5-, back flow reaction 2h.Naturally cooling, is chilled to room temperature, separates out white precipitate, and suction filtration obtains white and product 14.5g.Use 140ml recrystallizing methanol, obtain the L-mandelate that 13.1g refines the chloro-1-aminoidan of R-5-, yield is 43.5%.
(2) the chloro-1-aminoidan of R-5-is prepared
The L-mandelate 13.1g of the chloro-1-aminoidan of upper step gained R-5-is dissolved in 200ml water, drip ammonia soln and regulate pH value to 13,3 times are extracted by ethyl acetate (100ml, 50ml, 50ml), ethyl acetate layer merges, with water (50ml), saturated brine (50ml) respectively washing once, anhydrous sodium sulfate drying, filtration, concentratedly to obtain R-5-chloro-1-aminoidan 6.7g, yield is 40.1%, ee value is 99.1%.
(3) resolving agent L-amygdalic acid reclaims
Split and steam except methyl alcohol with recrystallization mother liquor.After cooling, by alkalizing in the mother liquor after concentrated and step 2, remaining aqueous layer afterwards concentrates in together, sulphuric acid soln is used to regulate pH value to 3, with ethyl acetate (150ml, 100ml, 50ml) extract 3 times, ethyl acetate merges, and with water (50ml), saturated brine (50ml) respectively washs once, anhydrous sodium sulfate drying, filtration, concentrated obtaining L-amygdalic acid 16.8, yield is 92.3%.
Claims (7)
1. the invention discloses preparation method's method of the chloro-1-aminoidan of a kind of R-5-, the present invention is with the chloro-1-indone of 5-for starting raw material, in alcoholic solvent, generate ketoxime with azanol and alkali reaction, and ketoxime obtains the chloro-1-aminoidan of 5-through hydrogenation catalyst shortening; Upper step gained 5-chloro-1-aminoidan and a certain amount of chiral selectors L-amygdalic acid react in suitable alcoholic solution, cooling, crystallization, suction filtration obtain the L-mandelate of the chloro-1-aminoidan of R-5-, after salt recrystallization purifying, be dissolved in the water, operate to obtain the chloro-1-aminoidan of R-5-through alkalization, extraction, drying, concentrate etc., and the ee value of the chloro-1-aminoidan of gained R-5-is greater than 99%; Raffinate containing L-amygdalic acid composition used merges together, and operate recyclable L-amygdalic acid through acidifying, extraction, drying, concentrate etc., its reaction equation is as follows:
2. a kind of method preparing the chloro-1-aminoidan of R-5-according to claim 1, is characterized in that: preparation 5-chloro-1-indanone oxime azanol used is oxammonium hydrochloride, and alkali used is sodium-acetate, and reaction solvent for use is methyl alcohol or ethanol.
3. a kind of method preparing the chloro-1-aminoidan of R-5-according to claim 1, is characterized in that: the hydrogenation catalyst that ketoxime hydrogenating reduction prepares 5-chloro-1-aminoidan used is Raney's nickel, and it drops into the 5%-20% that quality is 5-chloro-1-indone quality.
4. a kind of method preparing the chloro-1-aminoidan of R-5-according to claim 1, is characterized in that: splitting R-5-chloro-1-aminoidan resolving agent used is L-amygdalic acid, and the molar ratio of raw material and resolving agent is 1:1.0 ~ 2.0.
5. a kind of method preparing the chloro-1-aminoidan of R-5-according to claim 1, is characterized in that: split and solvent that recrystallization reacts used is methyl alcohol or ethanol, and the mass ratio that feeds intake of raw material and solvent is 10 ~ 30.
6. a kind of method preparing the chloro-1-aminoidan of R-5-according to claim 1, is characterized in that: salinization process alkali used is sodium hydroxide solution or ammonia soln.
7. a kind of method preparing the chloro-1-aminoidan of R-5-according to claim 1, is characterized in that: when reclaiming resolving agent, acidification acid used is hydrochloric acid or sulphuric acid soln.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510529757.4A CN105085279A (en) | 2015-08-26 | 2015-08-26 | Preparation of R-5-chloro-1-aminoindane |
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| CN201510529757.4A CN105085279A (en) | 2015-08-26 | 2015-08-26 | Preparation of R-5-chloro-1-aminoindane |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5639913A (en) * | 1994-01-10 | 1997-06-17 | Teva Pharmaceutical Industries, Ltd. | Method for preparing optically active 1-aminoindan derivatives |
| WO2008063671A2 (en) * | 2006-11-20 | 2008-05-29 | Alantos Pharmaceuticals Holding, Inc. | Heterobicyclic metalloprotease inhibitors |
| CN101516850A (en) * | 2006-08-08 | 2009-08-26 | 米伦纽姆医药公司 | Heteroaryl compounds useful as inhibitors of E1 activating enzymes |
-
2015
- 2015-08-26 CN CN201510529757.4A patent/CN105085279A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5639913A (en) * | 1994-01-10 | 1997-06-17 | Teva Pharmaceutical Industries, Ltd. | Method for preparing optically active 1-aminoindan derivatives |
| CN101516850A (en) * | 2006-08-08 | 2009-08-26 | 米伦纽姆医药公司 | Heteroaryl compounds useful as inhibitors of E1 activating enzymes |
| WO2008063671A2 (en) * | 2006-11-20 | 2008-05-29 | Alantos Pharmaceuticals Holding, Inc. | Heterobicyclic metalloprotease inhibitors |
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Application publication date: 20151125 |