CN1557809A - Process for synthesis of chiral oxazolidine-2-thioketone compounds - Google Patents
Process for synthesis of chiral oxazolidine-2-thioketone compounds Download PDFInfo
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- CN1557809A CN1557809A CNA2004100160153A CN200410016015A CN1557809A CN 1557809 A CN1557809 A CN 1557809A CN A2004100160153 A CNA2004100160153 A CN A2004100160153A CN 200410016015 A CN200410016015 A CN 200410016015A CN 1557809 A CN1557809 A CN 1557809A
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Abstract
The present invention is the high efficiency and low cost synthesis process of chiral oxazolidine-2-thione compound. The compound is prepared with chiral amino alcohol and through successive reaction with carbon disulfide and hydrogen peroxide in the presence of inorganic alkali in the same container.
Description
Technical field
The present invention relates to the new efficient cheap synthetic method of class Shou oxazolidine-2-thioketones (Chiral oxazolidine-2-thiones) compound.
Background technology
Shou oxazolidine-2-thioketones is used for synthesizing chiral compound as the chirality prothetic group just has report (referring to (a) A review:Fujita, E. in twentieth century eight, the nineties; Nagao, Y.Adv.Heterocyl.Chem.1989,45,1-36. (b) Garcia-Fernandez, J.M.; Ortiz-Mellet, C.; Fuentes, J.J.Org.Chem.1993,58,5192-5199. (c) Nagao, Y.; Kumagai, T.; Nagase, Y.; Tamai, S.; Inoue, Y.; Shiro, M.J.Org.Chem.1992,57,4232-4237. (d) Crimmins, M.T.; King, B.W.; Tabet, E.A.J.Am.Chem.Soc.1997,119,7883-7884.).Wherein 4-Dan substituted oxazole alkane-2-thioketones class prothetic group is owing to the outstanding performance (document d) in asymmetric aldol reaction (can generate two chiral centres in single step reaction) is extremely being paid attention to especially in recent years.This is because 4-Dan substituted oxazole alkane-2-thioketones prothetic group is can role in asymmetric reaction identical Yu Chuan Tong De oxazolidine-2-ketone prothetic group (be the Evans prothetic group---be one of the instrument of most important, the most sophisticated introducing chirality in the modern organic synthesis), but the excision stage after finishing chiral induction has outstanding advantage---excise easily than Xiang Ying De oxazolidine-2-ketone prothetic group.This point is very estimable advantage in the chirality of complicated sensitive molecule is complete synthesis.
Because the vital role of 4-Dan substituted oxazole alkane-2-thioketones prothetic group in chirality is synthetic, seek its cheapness, synthetic method seems very necessary efficiently.Maximum synthetic this compounds method of quoting in the literature at present is that LeCorre etc. is at nineteen ninety-five report (Delaunay, D.; Toupet, L.; Le Corre, M.J.Org.Chem.1995,60,6604-6607): in methylene dichloride, reflux in the presence of triethylamine with chiral amino alcohol and to spend the night, again in the mixed system of the NaOH aqueous solution and tetrahydrofuran (THF) with dithiocarbonic anhydride backflow 1h (formula 1)
Formula 1.
Or with 1N Na
2CO
3The aqueous solution, the two-phase system backflow 15min (formula 2) of amino alcohol and dithiocarbonic anhydride.
Formula 2
Preceding a kind of method will be in two steps, the time also long (flash-point of dithiocarbonic anhydride and boiling point are all very low, and long-time the backflow is easy to accidents happened to).Though a kind of method time of back is very short, always can't avoid the formation of by product sulphur zolidine thione.The existence of this by product has caused the difficulty of separation and purification inevitably.Synthetic report ((a) Nagao, the Y. of other relevant 4-Dan substituted oxazole alkane-2-thioketones in the document; Kumagai, T.; Yamada, S.; Fujita, E.J.Chem.Soc.PerkinTrans l 1985,2361-2367. (b) Cuzzupe, A.N.; Hutton, C.A.; Lilly, M.J.; Mann, R.K.; McRae, K.J.; Zammit, S.C.; Rizzacasa, M.A.J.Org.Chem.2001,66,2382-2393. (c) Isobe, T.; Ishikawa, T.J.Org.Chem.1999,64,6989-6992. (d) Moreno-Manas, M.; Padros, I.J.Heterocycl.Chem.1993,30,1235-1239.).Document a wherein, the method for b and d and Le Corre roughly the same (with chiral amino alcohol in the presence of triethylamine, in methylene dichloride, reflux a few hours or spend the night).Although the crude product yield of document d report is 100% (not reporting any purity parameter), the paper (having quoted document d) of the Le Corre that delivers after 2 years is not difficult to find out, document d results reported is problematic, otherwise Le Corre can't report that its two-step approach is (promptly at the 1h that refluxes again on the basis of document d again in the system of the NaOH aqueous solution and THF.)。The reaction that we repeat document d also finds only to reflux tens hours, and reaction really is very incomplete.Though the method yield height of document c, owing to used expensive special reagent chlorination 2-chloro-1,3-dimethyl-imidazoles (2-chloro-1,3-dimethyl-ylimidazolinium chloride) practical value is had a greatly reduced quality.The Crimmins group (they use the method for above-mentioned Le Corre always before this) that introduces the asymmetric aldol reaction of 4-Dan substituted oxazole alkane-2-thioketones prothetic group inductive has at first reported method (Crimmins, the M.T. that synthesizes 4-Dan substituted oxazole alkane-2-thioketones prothetic group with thio phosgene (thiophosgene) calendar year 2001; King, B.W.; Tabet, E.A.Chaudhary, K.J.Org.Chem.2001,66,894-902.), be reflected at 0 ℃ and just can finish very soon, and yield is very high because thio phosgene is much more active than dithiocarbonic anhydride.Yet the toxicity of thio phosgene is very big, and price is also high, has brought restriction for inevitably the application of this method.
People and report (Li, G. in 1997 such as Li; Tajima, H.; Ohtani, T.J.Org.Chem.1997,62,4539-4540.) can promote dithiocarbonic anhydride and primary amine reaction to generate different sulphur eyeball acid esters (isothiocyanates) with hydrogen peroxide.The same year their (Li, G.; Ohtani, T.Heterocycles 1997,45,2471-2474.) again this method are used for synthetic (the not mentioned chirality prothetic group of the whole work notion) of following five kinds of compounds:
Compd A wherein, B, E are not chipal compounds.The activity of the possible tool chirality prothetic group of Compound C and D, but because corresponding raw material amino alcohol cost is higher, the volume of substituting group (ethyl or methyl) that is used for producing asymmetric induction simultaneously is less, its asymmetric induction effect is certainly not as good as sec.-propyl, phenyl, or benzyl is greater, and Compound C and D are by sec.-propyl less than 4 as the effect of chirality prothetic group, phenyl, or benzyl Dan replaces De oxazolidine-2-thioketones.The work of above-mentioned Li has been quoted for several times by other people since 1997 deliver (comprising the synthetic paper of other hand oxazolidine-2-thioketones of report: (a) Ortiz, A.; Quintero, J.; Hernandez, H.; Maldoado, S.; Mendoza, G.; Bernes, S.Tetrahedron Lett.2003,44,1129-1132. (b) Ortiz, A.; Quintero, L.; Mendoza, G.; Bernes, S.Tetrahedron Lett.2003,44,5053-5055.), but the method with Li of not seeing all the time (for example: synthetic report three kinds of 4-Dan substituted oxazole alkane-2-thioketones that can be used as the chirality prothetic group that the present invention is included) is used for the Shou oxazolidine-2-thioketones of modern asymmetric synthesis practical application.
The method of above-mentioned Li adopts triethylamine and methyl alcohol as alkali and solvent respectively.The toxicity of these two kinds of compounds is all bigger, and wherein the price of triethylamine is also higher.Owing to used triethylamine, last handling process is also complicated.
Summary of the invention
The purpose of this invention is to provide a kind of efficient, simple and direct, convenient, cheap method for preparing chirality 4-Dan substituted oxazole alkane-2-thioketones prothetic group.
Method of the present invention can be represented by following reaction formula:
Wherein when R was H (hydrogen), R ' was sec.-propyl, phenyl or benzyl, and when R ' was H (hydrogen), R was sec.-propyl, phenyl or benzyl.
This method is by chiral amino alcohol
In the presence of mineral alkali successively with dithiocarbonic anhydride and hydroperoxidation and prepare the Shou oxazolidine-2-thioketone of tool said structure:
Wherein R, R ' are as previously mentioned.
Specifically, reaction conditions of the present invention is recommended as follows: adopt chiral amino alcohol in the presence of mineral alkali, in organic solvent, react 0.01-2h with dithiocarbonic anhydride at-40 ℃ to+100 ℃, add hydrogen peroxide subsequently, get the single substituted oxazole alkane of chirality 4--2-thioketones at-40 ℃ to+100 ℃ reaction 0.01-2h again, yield is 95-100%.Described chiral amino alcohol is
Wherein when R was H (hydrogen), R ' was sec.-propyl, phenyl or benzyl, and when R ' was H (hydrogen), R was sec.-propyl, phenyl or benzyl.Used mineral alkali in the inventive method: amino alcohol: dithiocarbonic anhydride: the mol ratio of hydrogen peroxide is recommended as 0.1-10: 1: 0.5-10: 0.5-10, temperature of reaction is recommended as-40 ℃ to+100 ℃, described mineral alkali is recommended as the carbonate of basic metal or alkaline-earth metal, supercarbonate or oxyhydroxide is sodium bicarbonate for example, saleratus, yellow soda ash, salt of wormwood, sodium hydroxide, potassium hydroxide, described hydrogen peroxide can be the aqueous solution or the crystallization that forms with urea (hydrogen peroxide-urea), the content of hydrogen peroxide of described aqueous hydrogen peroxide solution is recommended as 3%-85%, described organic solvent is recommended tetrahydrofuran (THF), acetonitrile, ethanol, Virahol etc.
Above-mentioned reaction mixture reach room temperature can the back with removing by filter solid shape insolubles, add organic solvent and water to filtrate again, tell organic layer after, boil off behind the organic solvent chirality 4-list substituted oxazole alkane-2-thioketones.Described organic solvent is recommended toluene, methylene dichloride, trichloromethane, ethyl acetate.Consumption of organic solvent is recommended as every mmole chiral amino alcohol 1-50mL.
Compare with existing ownership system Preparation Method, the inventive method has easy and simple to handle, safety, characteristics such as with low cost.
Embodiment
Following embodiment will help to understand the present invention, but not limit content of the present invention.
Embodiment 1
Cooling (5 ℃) stir down to chiral amino alcohol 1 (1.37g, 10mmol), salt of wormwood (1.4g, 10mmol), add in the mixture of ethanol (10mL) dithiocarbonic anhydride (0.6mL, 10mmol).The continuation stirring adds hydrogen peroxide after 0.1 hour (30%, 1.7mL 15mmol) continues to stir 0.1 hour at 30 ℃ again.Remove by filter insoluble solid matter.Wash (3 times) with water after adding vinyl acetic monomer (50mL) dilution in the filtrate.After branch anhydrated mutually, organic phase anhydrous sodium sulfate drying, normal temperature vacuum rotary steam got (R)-4-phenyl-oxazolidine-2-thioketones 2 (white solid, 1.776g, 99% yield) after removing and desolvating.Fusing point (thermometer is not through proofreading and correct): 118-119 ℃ of .[α]
20 D-78.2 ° (c 0.21, CHCl
3). document (Delaunay, D.; Toupet, L.; Le Corre, M.J.Org.Chem.1995,60,6604-6607) Bao Dao fusing point and optically-active: 121-122 ℃; [α]
22 D-79.3 ° (c 0.21, CHCl
3). other spectroscopic datas conform to bibliographical information.
Embodiment 2
Under the stirring at room to chiral amino alcohol 3 (1.031g, 10mmol), yellow soda ash (0.53g, 5mmol), add in the mixture of THF (10mL) dithiocarbonic anhydride (1.2mL, 20mmol).The continuation stirring adds hydrogen peroxide after 0.5 hour (50%, 1.0mL 15mmol) continues to stir 0.01 hour at 60 ℃ again.Remove by filter insoluble solid matter.Add methylene chloride in the filtrate and wash (3 times) with water after (100mL) dilutes.After branch anhydrated mutually, organic phase anhydrous sodium sulfate drying, normal temperature got (S)-4-sec.-propyl-oxazolidines-2-thioketones 4 (oily matter, 1.30g, 90% yield) after removing solvent under reduced pressure.[α]
19 D-18.7 (c 0.38, CHCl
3). document (Cuzzupe, A.N.; Hutton, C.A.; Lilly, M.J.; Mann, R.K.; McRae, K.J.; Zammit, S.C.; Rizzacasa, M.A.J.Org.Chem.2001,66,2382-2393.): [α]
20 D-18.1 (c 0.41, CHCl
3).Other spectroscopic datas conform to bibliographical information.
Embodiment 3
Cooling (0 ℃) stir down to chiral amino alcohol 5 (1.031g, 10mmol), sodium bicarbonate (1.68g, 20mmol), add in the mixture of Virahol (30mL) dithiocarbonic anhydride (1.8mL, 30mmol).The continuation stirring adds hydrogen peroxide after 0.1 hour (30%, 3.4mL 30mmol) continues to stir 0.5 hour at 20 ℃ again.Remove by filter insoluble solid matter.Wash (3 times) with water after adding vinyl acetic monomer (100mL) dilution in the filtrate.After branch anhydrated mutually, organic phase anhydrous sodium sulfate drying, normal temperature got (S)-4-benzyl-oxazolidines-2-thioketones 6 (oily matter 1.919g, 99% yield) after removing solvent under reduced pressure.[α]
17 D-91.8 (c 2.93, CHCl
3). document (Delaunay, D.; Toupet, L.; Le Corre, M.J.Org.Chem.1995,60,6604-6607): [α]
22 D-93.03 (c 1.88, CHCl
3).Other spectroscopic datas conform to bibliographical information.
Claims (6)
1. efficient, the cheap synthetic method of the hand of the following structure of tool oxazolidine-2-thioketone:
Wherein when R was H (hydrogen), R ' was sec.-propyl, phenyl or benzyl, and when R ' was H (hydrogen), R was sec.-propyl, phenyl or benzyl, it is characterized in that by chiral amino alcohol
Successively with dithiocarbonic anhydride and hydroperoxidation and prepare, wherein R, R ' are as previously mentioned in the presence of mineral alkali.
2. synthetic method as claimed in claim 1 is characterized in that making by following method:
By chiral amino alcohol
Be raw material, wherein when R is H (hydrogen), R ' is sec.-propyl, phenyl or benzyl, when R ' is H (hydrogen), R is sec.-propyl, phenyl or benzyl, in the presence of mineral alkali, in organic solvent, react with dithiocarbonic anhydride, reaction times is 0.01-2h, and temperature of reaction is-40 ℃ to+100 ℃, adds hydroperoxidation subsequently again, reaction times is 0.01-2h, temperature of reaction is-40 ℃ to+100 ℃, gets chirality oxazolidine-2-thioketones, and used mineral alkali: amino alcohol: dithiocarbonic anhydride: the mol ratio of hydrogen peroxide is 0.1-10: 1: 0.5-10: 0.5-10.
3. synthetic method as claimed in claim 1 is characterized in that described reaction is to have used mineral alkali and hydrogen peroxide in same reaction vessel.
4. synthetic method as claimed in claim 1, it is characterized in that described mineral alkali is the carbonate of basic metal or alkaline-earth metal, supercarbonate or oxyhydroxide, described hydrogen peroxide can be the aqueous solution or the crystallization (urea-hydrogen peroxide) that forms with urea, described organic solvent is a tetrahydrofuran (THF), acetonitrile, ethanol, Virahol.
5. synthetic method as claimed in claim 1 is characterized in that described mineral alkali is sodium bicarbonate, yellow soda ash, salt of wormwood, saleratus, sodium hydroxide or potassium hydroxide.
6. synthetic method as claimed in claim 4, the content of hydrogen peroxide that it is characterized in that described aqueous hydrogen peroxide solution is 3%-85%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447602A (en) * | 2014-10-27 | 2015-03-25 | 上海应用技术学院 | Preparation method of high-purity 5-vinyl oxazolidine-2-thioketone |
| CN113024481A (en) * | 2021-03-11 | 2021-06-25 | 中南民族大学 | Preparation method of tartaric acid-derived chiral oxazolidine-2-thioketone |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH09124621A (en) * | 1995-11-01 | 1997-05-13 | Shiratori Seiyaku Kk | Optically active 1,3-oxazolidine-2-thione derivative |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447602A (en) * | 2014-10-27 | 2015-03-25 | 上海应用技术学院 | Preparation method of high-purity 5-vinyl oxazolidine-2-thioketone |
| CN104447602B (en) * | 2014-10-27 | 2017-01-11 | 上海应用技术学院 | Preparation method of high-purity 5-vinyl oxazolidine-2-thioketone |
| CN113024481A (en) * | 2021-03-11 | 2021-06-25 | 中南民族大学 | Preparation method of tartaric acid-derived chiral oxazolidine-2-thioketone |
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