CN103524470B - The synthetic method of 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol - Google Patents
The synthetic method of 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol Download PDFInfo
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- ZNJANLXCXMVFFI-UHFFFAOYSA-N OC(C(CC1)Oc(cc2)c1cc2F)=O Chemical compound OC(C(CC1)Oc(cc2)c1cc2F)=O ZNJANLXCXMVFFI-UHFFFAOYSA-N 0.000 description 1
- OQJQDVVGBXXFML-UHFFFAOYSA-N [O-][N+](CC(C(CC1)Oc(cc2)c1cc2F)=O)=O Chemical compound [O-][N+](CC(C(CC1)Oc(cc2)c1cc2F)=O)=O OQJQDVVGBXXFML-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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Abstract
The invention provides the synthetic method of a kind of 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol, is for starting raw material synthesis 6-fluorine chroman-2-formyl imidazoles (II) with 6-fluorine chroman-2-carboxylic acid (I); 1-(the fluoro-2-chromanyl of 6-)-2-nitro-1-ethyl ketone (III) is synthesized again with the 6-fluorine chroman-2-formyl imidazoles (II) obtained; Finally 1-(6-fluoro-2-chromanyl)-2-nitro-1-ethyl ketone (III) obtained is reduced and obtain 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol (IV).Method raw material of the present invention is easy to get, reaction conditions is gentle, easy and simple to handle, be more suitable for suitability for industrialized production.
Description
Technical field
The invention belongs to organic chemistry filed, relate to the preparation method of a kind of 2-amino-1-(the fluoro-2-chromanyl of-6-) alcohol compound.
Background technology
Two chiral centres are had in 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol molecule, can have four optical isomers, wherein (R)-2-amino-1-((S)-6-fluoro-2-chromanyl) ethanol and (R)-2-amino-1-(the fluoro-2-chromanyl of (R)-6-) ethanol are the important intermediate of synthesis cardiovascular agent nebivolol.Their synthetic method has been reported in the literature, wherein Tetrahedron (2000,56,6339) and organic chemistry (2008,28,511) reporting with p-fluorophenol is that raw material has synthesized allyl alcohol compound through polystep reaction, and then through epoxidation reaction, tosic acid esterification reaction, azido reaction and reduction reaction obtain product amino alcohol.
Document Synthesis (2007; (8); 1154-1158) reporting with p-fluorophenol is that raw material obtains corresponding glycol, resynthesis methanesulfonates through acetylization reaction, condensation and cyclization reaction and reduction reaction, and last ammonia solution obtains corresponding amino alcohol.
JournaloftheAmericanChemicalSociety (1998), 120,8340-8347 reports one to be oxidized the epoxide that obtains by cycloheptadiene and 2-hydroxyl-5-fluorine methyl phenyl ketone reacts, corresponding hydroxy aldehyde is obtained again through series reaction, hydroxy aldehyde is through reducing, reacting with phthalic diamide, and last hydrazinolysis obtains corresponding amino alcohol.
Other method of bibliographical information all with 6-fluorine chroman-2-carboxylic acid for raw material, first synthesize 6-fluorine chroman-2-formaldehyde, then through the corresponding amino alcohol of different Reactive Synthesis.As Chinese Journal of Pharmaceuticals 2006,37,289-292 reports with 6-fluorine chroman-2-formaldehyde and sodium cyanide addition, then hydrogenation obtains corresponding amino alcohol; Chinese patent CN101235024 utilizes 6-fluorine chroman-2-formaldehyde and Nitromethane 99Min. to react, and obtains corresponding amino alcohol through over hydrogenation.
It is long all to there is synthetic route in the various synthetic methods of bibliographical information, the limitation such as productive rate is low, and condition that some reaction requires is harsh, reacts wayward, is difficult to batch production.
Summary of the invention:
The object of the invention is to overcome that the reactions steps existed in existing bibliographical information is many, operation is complicated, severe reaction conditions, the problems such as yield is low, a kind of mild condition is provided, easy and simple to handle, synthetic route is short, be suitable for the route of synthesis 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol produced in batches.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
There is provided the synthetic method of a kind of 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol, its step is as follows:
1) with 6-fluorine chroman-2-carboxylic acid (I) for starting raw material synthesis 6-fluorine chroman-2-formyl imidazoles (II);
2) the 6-fluorine chroman-2-formyl imidazoles (II) obtained with step 1) synthesizes 1-(the fluoro-2-chromanyl of 6-)-2-nitro-1-ethyl ketone (III);
3) by step 2) 1-(6-fluoro-2-chromanyl)-2-nitro-1-ethyl ketone (III) that obtains reduces obtained 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol (IV);
Its overall synthetic route is as follows:
In synthetic method of the present invention, the 6-fluorine chroman-2-carboxylic acid described in step 1) can be S-configuration, R-configuration or raceme.
In synthetic method of the present invention, as follows with the synthetic route of 6-fluorine chroman-2-carboxylic acid synthesis 6-fluorine chroman-2-formyl imidazoles described in step 1):
This synthetic route can by based on the accomplished in many ways of prior art, any one preferably in following two kinds of methods of the present invention:
6-fluorine chroman-2-carboxylic acid and carbonyl dimidazoles mix post-heating in organic solvent with the mol ratio of 1:1 ~ 2 and reflux and within 1 ~ 5 hour, obtain 6-fluorine chroman-2-formyl imidazoles;
Or,
6-fluorine chroman-2-carboxylic acid and sulfur oxychloride mix post-heating in organic solvent with the mol ratio of 1:1 ~ 5 and reflux and obtain corresponding acyl chlorides in 1 ~ 5 hour, more corresponding acyl chlorides and imidazoles are reacted in organic solvent by the mol ratio of 1:1 ~ 2 and within 1 ~ 5 hour, obtain 6-fluorine chroman-2-formyl imidazoles.
Described organic solvent can be tetrahydrofuran (THF), methylene dichloride, toluene, chloroform, Isosorbide-5-Nitrae-dioxane, DMF, methyl-sulphoxide etc.; Preferred tetrahydrofuran (THF), toluene or methylene dichloride.
The weight ratio of described organic solvent and 6-fluorine chroman-2-carboxylic acid is preferably 5 ~ 50:1.
In synthetic method of the present invention, step 2) described in as follows with the synthetic route of 6-fluorine chroman-2-formyl imidazoles synthesis 1-(6-fluoro-2-chromanyl)-2-nitro-1-ethyl ketone:
This synthetic route can by the accomplished in many ways based on prior art; the preferred synthesis step of the present invention is that Nitromethane 99Min. is dissolved in organic solvent; add highly basic; stirring at room temperature 1 ~ 5 hour; then the acylimidazole compound (II) that step 1) is obtained is added; heating reflux reaction 3 ~ 20 hours; be cooled to room temperature, add water; with acid for adjusting pH value to acid; extraction, washing; organic phase is dry, and revolve steaming and obtain crude product, crude product obtains white solid 1-(the fluoro-2-chromanyl of 6-)-2-nitro-1-ethyl ketone (III) through recrystallization.
Organic solvent used can be tetrahydrofuran (THF), methylene dichloride, toluene, chloroform, Isosorbide-5-Nitrae-dioxane, DMF, methyl-sulphoxide, ether, t-butyl methyl ether etc.; Preferred tetrahydrofuran (THF) or methylene dichloride.
The weight ratio of described organic solvent and acylimidazole compound (II) is 5 ~ 50:1.
Described extraction agent can be ethyl acetate, methylene dichloride, chloroform etc., and the consumption of extraction agent and the volume ratio of reaction solvent are 1:1 ~ 5.
Described highly basic can be selected from potassium tert.-butoxide, sodium hydride, sodium hydroxide, sodium tert-butoxide, sodium ethylate, sodium methylate etc.; Preferred potassium tert.-butoxide.
In synthetic method of the present invention, the reduction reaction route described in step 3) is as follows:
Described reduction can adopt metal hydride reduction, or metal catalyst catalytic hydrogen reduction.
Described metal hydride reduction method is preferred: by step 2) 1-(the fluoro-2-chromanyl of 6-)-2-nitro-1-ethyl ketone (III) that obtains is dissolved in organic solvent, the metal hydride reducing agent suspension liquid in organic solvent of organic solvent instillation under ice-water bath cooling of 1-(the fluoro-2-chromanyl of 6-)-2-nitro-1-ethyl ketone will be dissolved with, compound (III) is made to reach 1:1 ~ 5 with the mol ratio of metal hydride reducing agent, react 2 ~ 10 hours, water termination reaction is slowly added under ice-water bath cooling, with organic solvent extraction 3 times, dry organic layer, revolve steaming and obtain crude product, recrystallization obtains 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol (IV).
The mixture of the preferred lithium aluminum hydride of described metal hydride reducing agent, red aluminium (Red-Al) or sodium borohydride and inorganic salt; The preferred nickel acetate of described inorganic salt.
Described reductive agent be lithium aluminum hydride or Red-Al time, organic solvent can be tetrahydrofuran (THF), ether, t-butyl methyl ether, toluene, Isosorbide-5-Nitrae-dioxane etc.; Preferred tetrahydrofuran (THF) or toluene.
When described reductive agent is the mixture of sodium borohydride and inorganic salt, organic solvent used can be tetrahydrofuran (THF), toluene, methyl alcohol, ethanol, Virahol, Isosorbide-5-Nitrae-dioxane, DMF etc.; Preferred tetrahydrofuran (THF) or methyl alcohol.
The weight ratio of described solvent and 1-(the fluoro-2-chromanyl of 6-)-2-nitro-1-ethyl ketone (III) is 5 ~ 50:1.
Described metal catalyst catalytic hydrogen reduction method is preferred: the step 2 by 1 molfraction) 1-(the fluoro-2-chromanyl of 6-)-2-nitro-1-ethyl ketone (III) that obtains is dissolved in organic solvent, add the metal catalyst of 0.2 molfraction, then the ammonium formiate passing into hydrogen or add 5 molfractions reduces, and aftertreatment obtains 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol (IV).
Described metal catalyst can be palladium carbon, platinum carbon or Raney nickel.
Described solvent can be methyl alcohol, ethanol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ethyl acetate or acetic acid etc.
The all raw materials used in synthetic method of the present invention are existing compound, or can prepare according to existing method.
Compared with prior art, the present invention propose 2-amino-1-(-6-fluoro-2-chromanyl) ethanol synthetic method mild condition, easy and simple to handle, synthetic route is short, be suitable for batch production.
Specific implementation method
Below by the concrete example implemented, the present invention is described further.
Embodiment 1
6-fluorine chroman-2-carboxylic acid (1g) is dissolved in THF (10mL), adds carbonyl dimidazoles (1g) under stirring at room temperature, mixture reflux 1 ~ 5 hour, obtains acylimidazole solution.Potassium tert.-butoxide (1g) is mixed with THF (15mL), instills Nitromethane 99Min. (2mL) under stirring at room temperature, stirring at room temperature 1 ~ 5 hour.Acylimidazole solution is mixed with nitromethane solution; reflux 3 ~ 20 hours; cool, add water (50mL), with salt acid for adjusting pH value to acid, add ethyl acetate (50mL) extraction; organic phase washing, drying; revolve and steam except desolventizing obtains crude product, crude product ethyl alcohol recrystallization obtains white solid (III) (0.92g, yield 75%); fusing point 69 ~ 71 DEG C
1hNMR (400MHz, CDCl
3) δ 2.08-2.13 (m, 1H), 2.33-2.35 (m, 1H), 2.80-2.89 (m, 2H), 4.69 (dd, J=9.5,3.2Hz, 1H), 5.52 (d, J=16.0Hz, 1H), 5.68 (d, J=16.0Hz, 1H), 6.78-6.86 (m, 3H).
Embodiment 2
6-fluorine chroman-2-carboxylic acid (1g) is mixed with toluene (10mL), adds thionyl chloride (1mL), load onto gas absorbing device, reflux 1 ~ 5 hour.Removal of solvent under reduced pressure and unreacted thionyl chloride, add methylene dichloride (10mL), adds imidazoles (0.7g), stirring at room temperature 1 ~ 5 hour.Potassium tert.-butoxide (1g) is mixed with THF (15mL), instills Nitromethane 99Min. (2mL) under stirring at room temperature, stirring at room temperature 1 ~ 5 hour.Acylimidazole solution is mixed with nitromethane solution; reflux 3 ~ 20 hours; cool, add water (50mL), with salt acid for adjusting pH value to acid, add ethyl acetate (50mL) extraction; organic phase washing, drying; revolve and steam except desolventizing obtains crude product, crude product ethyl alcohol recrystallization obtains white solid (III) (0.98g, yield 80%); fusing point 69 ~ 71 DEG C
1hNMR (400MHz, CDCl
3) δ 2.08-2.13 (m, 1H), 2.33-2.35 (m, 1H), 2.80-2.89 (m, 2H), 4.69 (dd, J=9.5,3.2Hz, 1H), 5.52 (d, J=16.0Hz, 1H), 5.68 (d, J=16.0Hz, 1H), 6.78-6.86 (m, 3H).
Embodiment 3
Product (III) (0.92g) that embodiment 1 obtained is dissolved in THF(20mL), instill in lithium aluminum hydride (0.4g) under ice-water bath cooling and mixed solution THF(20mL), continue stirring 1 ~ 5 hour.Slowly add water termination reaction, with dichloromethane extraction three times, extraction liquid is dry, revolves steaming and obtains product 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol (IV) (0.51g, yield 63%).
1HNMR(400MHz,CDCl
3)δ1.87-1.99(m,4H),2.73-3.00(m,4H),3.63-3.67(m,1H),3.94-3.98(m,1H),6.73-6.79(m,3H)。
Embodiment 4
Product (III) (0.35g) that embodiment 2 obtained is dissolved in methyl alcohol, adds Pd/C(0.1g), then add sodium borohydride (0.3g), stirring at room temperature 2 ~ 10 hours.Filtration of catalyst, water and methylene dichloride is added after mother liquor concentrations, separate organic layer, water layer dichloromethane extraction 2 times, merge organic phase, anhydrous sodium sulfate drying, revolves steaming and obtains solid, product 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol (IV) is obtained, productive rate 45% through recrystallization.
1HNMR(400MHz,CDCl
3)δ1.87-1.99(m,4H),2.73-3.00(m,4H),3.63-3.67(m,1H),3.94-3.98(m,1H),6.73-6.79(m,3H)。
Embodiment 5
Product (III) (0.35g) that embodiment 2 obtained is dissolved in methyl alcohol (10mL), adds nickelous chloride (0.1g), then adds sodium borohydride (0.3g) in batches, stirring at room temperature 1 ~ 5 hour.Add water termination reaction, adds dichloromethane extraction three times, Filtration of catalyst, and mother liquor concentrations obtains solid (IV), productive rate 53%.
1HNMR(400MHz,CDCl
3)δ1.87-1.99(m,4H),2.73-3.00(m,4H),3.63-3.67(m,1H),3.94-3.98(m,1H),6.73-6.79(m,3H)。
Claims (4)
1. a synthetic method for 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol, its step is as follows:
(1) with 6-fluorine chroman-2-carboxylic acid (I) for starting raw material synthesis 6-fluorine chroman-2-formyl imidazoles (II):
6-fluorine chroman-2-carboxylic acid and sulfur oxychloride are mixed post-heating in organic solvent with the mol ratio of 1:1 ~ 5 reflux and obtain corresponding acyl chlorides in 1 ~ 5 hour, more corresponding acyl chlorides and imidazoles are reacted in organic solvent by the mol ratio of 1:1 ~ 2 within 1 ~ 5 hour, obtain 6-fluorine chroman-2-formyl imidazoles; Described organic solvent all can be selected from tetrahydrofuran (THF), methylene dichloride, toluene, chloroform, Isosorbide-5-Nitrae-dioxane, DMF or methyl-sulphoxide; The weight ratio of described organic solvent and 6-fluorine chroman-2-carboxylic acid is 5 ~ 50:1;
(2) with 6-fluorine chroman-2-formyl imidazoles synthesis 1-(the fluoro-2-chromanyl of 6-)-2-nitro-1-ethyl ketone (III) that step (1) obtains:
Nitromethane 99Min. is dissolved in organic solvent, add highly basic, stirring at room temperature 1 ~ 5 hour, then adds step 1) obtained 6-fluorine chroman-2-formyl imidazoles, heating reflux reaction 3 ~ 20 hours, be cooled to room temperature, add water, with acid for adjusting pH value to acid, extraction, washing, organic phase is dry, revolve steaming and obtain crude product, crude product obtains white solid 1-(the fluoro-2-chromanyl of 6-)-2-nitro-1-ethyl ketone through recrystallization;
Described organic solvent is tetrahydrofuran (THF), methylene dichloride, toluene, chloroform, Isosorbide-5-Nitrae-dioxane, DMF, methyl-sulphoxide, ether or t-butyl methyl ether; The weight ratio of organic solvent and 6-fluorine chroman-2-formyl imidazoles is 5 ~ 50:1;
Described extraction agent is ethyl acetate, methylene dichloride or chloroform; The consumption of extraction agent and the volume ratio of reaction solvent are 1:1 ~ 5;
Described highly basic is selected from potassium tert.-butoxide, sodium hydride, sodium hydroxide, sodium tert-butoxide, sodium ethylate or sodium methylate;
(3) 1-(6-fluoro-2-chromanyl)-2-nitro-1-ethyl ketone step (2) obtained adopts metal catalyst catalytic hydrogen reduction to obtain 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol (IV):
Step 2 by 1 molfraction) 1-(the fluoro-2-chromanyl of the 6-)-2-nitro-1-ethyl ketone that obtains is dissolved in organic solvent, add the metal catalyst of 0.2 molfraction, then the ammonium formiate passing into hydrogen or add 5 molfractions reduces, and aftertreatment obtains 2-amino-1-(the fluoro-2-chromanyl of-6-) ethanol (IV); Described metal catalyst is palladium carbon, platinum carbon or Raney nickel; Described organic solvent is methyl alcohol, ethanol, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, ethyl acetate or acetic acid;
Its overall synthetic route is as follows:
2. synthetic method according to claim 1, the organic solvent described in step (1) is tetrahydrofuran (THF), toluene or methylene dichloride.
3. synthetic method according to claim 1, the organic solvent described in step (2) is tetrahydrofuran (THF) or methylene dichloride.
4. synthetic method according to claim 1, the highly basic described in step (2) is potassium tert.-butoxide.
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| WO2003018546A2 (en) * | 2001-08-21 | 2003-03-06 | Merck Sharp & Dohme Limited | Tricyclic pyridin-2-one analogues as ligands for gaba-a receptors |
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| WO2011061675A1 (en) * | 2009-11-18 | 2011-05-26 | Piramal Healthcare Limited | Process for enantioselective preparation of nitroketone, an intermediate of protease inhibitors |
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| WO2003018546A2 (en) * | 2001-08-21 | 2003-03-06 | Merck Sharp & Dohme Limited | Tricyclic pyridin-2-one analogues as ligands for gaba-a receptors |
| CN101235024A (en) * | 2008-02-01 | 2008-08-06 | 中国科学院上海有机化学研究所 | Benzodihydropyrane compounds, synthesizing method and use thereof |
| WO2011061675A1 (en) * | 2009-11-18 | 2011-05-26 | Piramal Healthcare Limited | Process for enantioselective preparation of nitroketone, an intermediate of protease inhibitors |
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Address after: 100875, 19, Xinjie street, Haidian District, Beijing Patentee after: BEIJING NORMAL University Patentee after: Beijing Shihong Pharmaceutical Co., Ltd Address before: 100875, 19, Xinjie street, Haidian District, Beijing Patentee before: BEIJING NORMAL University Patentee before: Beijing Shihong drug development center |