CN102584620B - The preparation method of alpha-amino ketone derivative - Google Patents
The preparation method of alpha-amino ketone derivative Download PDFInfo
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- CN102584620B CN102584620B CN201110002066.0A CN201110002066A CN102584620B CN 102584620 B CN102584620 B CN 102584620B CN 201110002066 A CN201110002066 A CN 201110002066A CN 102584620 B CN102584620 B CN 102584620B
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Abstract
The invention discloses the preparation method such as formula the alpha-amino ketone derivative shown in II, in organic solvent, react such as formula the compound shown in I under the effect of TCCA (Trichloroisocyanuric acid), oxide catalyst; Or, in organic solvent, be under the condition of 8 ~ 11 at pH, react such as formula the compound shown in I under the effect of oxygenant, oxide catalyst, pH adjusting agent and phase-transfer catalyst; Wherein, R
1, R
2and R
3be low alkyl group independently, aryl, aryl replace low alkyl group, lower alkoxy, lower alkoxy that aryl replaces, carboxyl substituted low alkyl group or connect the carbonyl of low alkyl group; R
4for connecting the carbonyl of the low alkyl group that the carbonyl of low alkyl group, the carbonyl connecting aryl or connection phenyl replace.Preparation method's cheaper starting materials of the present invention is easy to get, reaction conditions gentle, environmental pollution is little, and feed stock conversion is high, is conducive to industrial mass production.
Description
Technical field
The present invention relates to the preparation method of alpha-amino ketone derivative.
Background technology
Pseudoephedrine is the main composition of multiple pills for preventing common cold, and clinical practice for many years shows, it is one medicine safely and effectively, applies all quite extensive at present at home and abroad.
In the recrystallization mother liquor of pseudoephedrine production process, only containing have an appointment 5% (1S, 2S) type pseudoephedrine, about 95% is its (1R, 2R) type isomer.How unwanted (1R, 2R) type isomer being converted into useful (1S, 2S) configuration, is an important topic urgently to be resolved hurrily in suitability for industrialized production.Conventional method for transformation by oxidation, heating racemization, reduction, acylated hydroxy, isomerization, be hydrolyzed, add alkali and to dissociate and the sequence of operations step such as fractionation realizes.Wherein, the selection of method for oxidation is a ring of most critical.
The conventional reagent being used for α-aminoalcohol to be oxidized to alpha-amino group ketone has manganese reagent, chromium reagent etc.These reagent oxidation are excessively strong, have a large amount of by product to generate in reaction, cause that product yield is not high, separation and purification is difficult; Meanwhile, owing to employing heavy metal, environmental pollution is serious.Therefore, ordinary method is unfavorable for industrial scale operation.
Nineteen eighty-two, the people such as Berrang, Bertold D report the method with chromium trioxide/oxidation of methylpyridine 1-phenyl-2-amino-1-propyl alcohol, and yield can reach 83%, but serious (Berrang, the Bertold D. of environmental pollution; Lewin, Anita H.; Carroll, F.Ivy; Journal of Organic Chemistry; Vol.47; Nb.13; (1982); P.2643-2647).Nineteen ninety-five, the people such as Frigerio, Marco disclose with methyl-sulphoxide or acetonitrile for solvent, and by the method for 2-iodosobenzoic acid/trifluoroacetic acid oxidation 1-phenyl-2-methylamino-1-propyl alcohol, yield can reach 90% (Frigerio, Marco; Santagostino, Marco; Sputore, Simona; Palmisano, Giovanni; Journal of Organic Chemistry; Vol.60; Nb.22; (1995); P.7272-7276), although the method use environmentally friendly oxygenant, yield is also higher, and solvent for use toxicity is large and be difficult to reclaim.Nineteen eighty-three, the people such as Zhestkov, V.P. are that oxygenant is oxidized 1-phenyl-2-(N-ethanoyl)-methylamino-1-propyl alcohol in acetic acid with clorox, and yield is 57% (ZhestkovV.P. only; Voronin V.G.; Portnov Yu.N.; Pharmaceutical Chemistry Journal; 1983; Vol.17, #9; P.657-660).
The oxidation of 2,2,6,6-tetramethyl piperidine-1-oxyradical (TEMPO) catalytic alcohol causes the attention of people to come from Aneli method.The method is usually at CH
2cl
2in, in 0 ~ 15 DEG C, under the condition of pH9, carry out at 1mol%TEMPO, 10mol%NaBr or KBr with under existing little over the NaClO solution of amount, primary, secondary alcohol can be all corresponding aldehydes or ketones by optionally Quick Oxidation.The people such as M.Robert Leanna report under these conditions, when amino is by radical protections such as tertbutyloxycarbonyl (Boc) or carbobenzoxy-(Cbz)s (Cbz), α-aminoalcohol can by Quick Oxidation, yield is 51 ~ 96% (M.Robert Leanna, Thomas J.Sowin and Howard E.Morton; Tetrahedron Letters, Vol.33; No.35; (1992); P.5029-5032).Wherein, when substrate is
time, yield is 96%.Although the method reaction conditions is gentle, solvent toxicity is little, easily reclaim, and the yield of reaction is unstable, and adds the operation of introducing and deprotection base, also reduces the efficiency of reaction while adding cost.
Therefore, need badly development a kind of reaction conditions gentle, easy and simple to handle, yield is high, by product is few, the eco-friendly method for oxidation being suitable for the α-aminoalcohol of suitability for industrialized production.
Summary of the invention
Technical problem to be solved by this invention be to overcome in prior art that reagent oxidation existing for the conventional method for α-aminoalcohol being oxidized to alpha-amino group ketone is excessively strong, side reaction seriously, the defect such as yield is not high, environmental pollution is serious, and provide a kind of method for oxidation of gentleness, the method reagent is cheap and easy to get, reaction temperature and, yield is high, environmental pollution is little, easy to operate, can be used for suitability for industrialized production.
The present inventor is through concentrating on studies; find with TCCA (Trichloroisocyanuric acid) (TCCA) as oxygenant; TEMPO or derivatives thereof is oxide catalyst, when reacting in conventional organic solvent, without the need to protecting amino; without the need to adding NaBr or KBr; also without the need to the pH value of regulation system, reaction can be carried out smoothly, and the yield of alpha-amino ketone derivative is about 97%; and temperature of reaction when changing between 0 ~ 40 DEG C, on reaction yield all without impact.In addition; in conventional organic solvent; in the presence of a phase transfer catalyst; with NaClO, HClO, hydrogen peroxide, peracid or persalt for oxygenant; with TEMPO or derivatives thereof for oxide catalyst, without the need to protecting amino, without the need to adding NaBr or KBr; reaction also can be carried out smoothly, and the yield of alpha-amino ketone derivative is about 84%.
Therefore, the present invention relates to a kind of preparation method such as formula the alpha-amino ketone derivative shown in II, it comprises the following step: in organic solvent, reacts such as formula the compound shown in I under the effect of TCCA (Trichloroisocyanuric acid), oxide catalyst;
Wherein, R
1, R
2and R
3be low alkyl group independently, aryl, aryl replace low alkyl group, lower alkoxy, lower alkoxy that aryl replaces, carboxyl substituted low alkyl group or connect the carbonyl of low alkyl group.
R
4for connecting the carbonyl of the low alkyl group that the carbonyl of low alkyl group, the carbonyl connecting aryl or connection phenyl replace.
Work as R
4during for connecting the carbonyl of low alkyl group, R
4be preferably ethanoyl, positive propionyl, iso-propionyl, positive butyryl radicals, isobutyryl or tertiary butyryl radicals.
Work as R
4during for connecting the carbonyl of low alkyl group that phenyl replaces, R
4it is preferably phenylacetyl.
Work as R
4during for connecting the carbonyl of aryl, R
4be preferably to toluyl or benzoyl.
Wherein, described oxide catalyst is for such as formula the compound shown in III:
Wherein, R
5and R
5' be low alkyl group independently.
R
6and R
7be all hydrogen atom or be all lower alkoxy; Or one is hydrogen atom, another is hydroxyl, low alkyl group, low alkyl group acyloxy, aryl acyloxy or N-(lower alkyl amide) amido; Or R
6and R
7together for the Ketal form shown in following formula a, formula b or formula c:
Wherein, R
8for low alkyl group.
R
9and R
9' be hydrogen atom or low alkyl group independently.
Y is for the group form shown in following formula d, formula e or formula f:
Wherein, X
-for fluorion, chlorion, bromide anion or iodide ion.
Wherein, described oxide catalyst is preferably 2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-carbonyl-2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-hydroxyl-2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-amino-2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-methoxyl group-2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-benzoyloxy-2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-acetylaminohydroxyphenylarsonic acid 2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-benzyl acyloxy-tetramethyl piperidine-1-oxyradical and 4-sulfonate group-2, 2, 6, one or more in 6-tetramethyl piperidine nitrogen oxygen free radical, better is 2,2,6,6-tetramethyl piperidine-1-oxygen base free radical.
Wherein, described oxide catalyst and the mol ratio of chemical compounds I are preferably 0.001: 3 ~ 2: 3; Better is 0.03: 3.
Wherein, described organic solvent can be the Conventional solvents of this type of reaction of this area, as: methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, pentyl acetate, methyl-formiate, ethyl formate, propyl formate, isopropyl formate, butyl formate, tetryl formate, pentyl formate, methyl propionate, ethyl propionate, propyl propionate, n-butyl propionate, isobutyl propionate, amyl propionate, benzene, toluene, hexanaphthene, methylene dichloride, trichloromethane, tetracol phenixin, 1, 2-ethylene dichloride, acetonitrile, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, one or more in ether and methyl tertiary butyl ether, ethyl acetate and/or toluene.The consumption of described organic solvent can be selected according to this area general knowledge; Preferably, described organic solvent is 5 ~ 30ml/g with the volume mass ratio of chemical compounds I.
Wherein, described TCCA (Trichloroisocyanuric acid) and the mol ratio of chemical compounds I are preferably 1: 3 ~ 10: 3, and better is 1.1: 3.
Wherein, the temperature of described reaction is preferably 10 ~ 40 DEG C.
Wherein, till time of described reaction preferably completes with detection reaction.
In the present invention, such as formula the preparation method of the alpha-amino ketone derivative shown in II, preferably comprise the following step: in organic solvent, react such as formula the compound shown in I and TCCA (Trichloroisocyanuric acid), oxide catalyst; Wherein, described organic solvent is preferably ethyl acetate and/or toluene; Described oxide catalyst is preferably 2,2,6,6-tetramethyl piperidine-1-oxyradical; Described in the consumption of the consumption of described organic solvent, the consumption of TCCA (Trichloroisocyanuric acid), oxide catalyst, the temperature and time of reaction are all the same.
The invention still further relates to a kind of preparation method such as formula the alpha-amino ketone derivative shown in II, it comprises the following step: in organic solvent, be under the condition of 8 ~ 11 at pH, react such as formula the compound shown in I under the effect of oxygenant, oxide catalyst, pH adjusting agent and phase-transfer catalyst;
Wherein, R
1, R
2and R
3be low alkyl group independently, aryl, aryl replace low alkyl group, lower alkoxy, lower alkoxy that aryl replaces, carboxyl substituted low alkyl group or connect the carbonyl of low alkyl group.
R
4for connecting the carbonyl of the low alkyl group that the carbonyl of low alkyl group, the carbonyl connecting aryl or connection phenyl replace.
Work as R
4during for connecting the carbonyl of low alkyl group, R
4be preferably ethanoyl, positive propionyl, iso-propionyl, positive butyryl radicals, isobutyryl or tertiary butyryl radicals.
Work as R
4during for connecting the carbonyl of low alkyl group that phenyl replaces, R
4it is preferably phenylacetyl.
Work as R
4during for connecting the carbonyl of aryl, R
4be preferably to toluyl or benzoyl.
Wherein, described oxide catalyst is for such as formula the compound shown in III:
Wherein, R
5and R
5' be low alkyl group independently.
R
6and R
7be all hydrogen atom or be all lower alkoxy; Or one is hydrogen atom, another is hydroxyl, low alkyl group, low alkyl group acyloxy, aryl acyloxy or N-(lower alkyl amide) amido; Or R
6and R
7together for the Ketal form shown in following formula a, formula b or formula c:
Wherein, R
8for low alkyl group.
R
9and R
9' be hydrogen atom or low alkyl group independently.
Y is for the group form shown in following formula d, formula e or formula f:
Wherein, X
-for fluorion, chlorion, bromide anion or iodide ion.
Wherein, described oxide catalyst is preferably 2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-carbonyl-2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-hydroxyl-2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-amino-2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-methoxyl group-2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-benzoyloxy-2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-acetylaminohydroxyphenylarsonic acid 2, 2, 6, 6-tetramethyl piperidine-1-oxyradical, 4-benzyl acyloxy-tetramethyl piperidine-1-oxyradical and 4-sulfonate group-2, 2, 6, one or more in 6-tetramethyl piperidine nitrogen oxygen free radical, better is 2,2,6,6-tetramethyl piperidine-1-oxyradical.Described oxide catalyst and the mol ratio of chemical compounds I are preferably 0.001: 1 ~ 0.1: 1, and better is 0.1: 1.
Wherein, described oxygenant is one or more in hydrogen peroxide, clorox, hypochlorous acid, peracid and persalt; Be preferably one or more in hydrogen peroxide, clorox and hypochlorous acid; Better is hydrogen peroxide and/or clorox.Described oxygenant and the mol ratio of chemical compounds I are preferably 1: 1 ~ 1.2: 1.
Wherein, described peracid is preferably permonosulphuric acid, peroxy-disulfuric acid, peracetic acid, cross valeric acid, cross in isovaleric acid, peroxyformic acid, Peracetic Acid, peroxy trifluoroacetic acid, Perpropionic Acid, Perbutyric Acid, peroxide isovaleric acid, benzoyl hydroperoxide, metachloroperbenzoic acid, nitroperoxybenzoic and monoperphthalic acid one or more.
Wherein, described persalt is preferably peroxy-monosulfate and/or peroxydisulfate.
Wherein, described phase-transfer catalyst is preferably one or more in crown ether, polyoxyethylene glycol, quaternary ammonium salt and season phosphonium salt.Described phase-transfer catalyst and the mol ratio of chemical compounds I are preferably 0.001: 1 ~ 0.1: 1.
Wherein, described crown ether is preferably one or more in 18-hat-6, dibenzo-18-crown-6 (DB18C6), cis-dicyclohexyl-18-crown-6,15-hat-5 and cyclodextrin.Described polyoxyethylene glycol is preferably PEG-200 and/or PEG-400.Described quaternary ammonium salt is preferably methyl triethyl ammonium chloride, methyl triethylammonium bromide, benzyl trimethyl ammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium hydroxide, benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide, tetramethyl ammonium chloride, 4 bromide, Tetramethylammonium iodide, Tetramethylammonium hydroxide, tetramethyl-monoammonium sulfate, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium iodide, TBAH, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, one or more in Dodecyl trimethyl ammonium chloride and tetradecyl trimethyl ammonium chloride.Described season phosphonium salt is preferably one or more in tetraphenylphosphonibromide bromide, triphenylmethylphosphonium bromide phosphine, triphenyl ethyl phosphonium bromide phosphine, triphenylbenzylphosphonium chloride phosphine, triphenyl propyl group bromide phosphine and triphenyl butyl bromide phosphine.
Wherein, described organic solvent can be the Conventional solvents of this type of reaction of this area, as: methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, pentyl acetate, methyl-formiate, ethyl formate, propyl formate, isopropyl formate, butyl formate, tetryl formate, pentyl formate, methyl propionate, ethyl propionate, propyl propionate, n-butyl propionate, isobutyl propionate, amyl propionate, benzene, toluene, hexanaphthene, methylene dichloride, trichloromethane, tetracol phenixin, 1, 2-ethylene dichloride, acetonitrile, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, one or more in ether and methyl tertiary butyl ether, ethyl acetate and/or toluene.The consumption of described organic solvent can be selected according to this area general knowledge; Preferably, described organic solvent is 5 ~ 30ml/g with the volume mass ratio of chemical compounds I.
Wherein, described pH adjusting agent is preferably NaHCO
3, Na
2cO
3, NaOH, KHCO
3, K
2cO
3, KOH, Ca (HCO
3)
2with Ca (OH)
2in one or more, that better is NaHCO
3.
Wherein, the pH of described reaction is preferably 8.8 ~ 9.2.
Wherein, the temperature of described reaction is preferably 10 ~ 40 DEG C.Till time of described reaction preferably completes with detection reaction.
In the present invention, such as formula the preparation method of the alpha-amino ketone derivative shown in II, preferably comprise the following step: in organic solvent, be under the condition of 8.8 ~ 9.2 at pH, react such as formula the compound shown in I under the effect of oxygenant, oxide catalyst, pH adjusting agent, phase-transfer catalyst; Wherein, described organic solvent is preferably ethyl acetate and/or toluene; Described oxygenant is preferably for hydrogen peroxide and/or clorox, described oxide catalyst are preferably 2,2,6,6-tetramethyl piperidine-1-oxyradicals; Described phase-transfer catalyst is preferably tetra-n-butyl ammonium bromide; Described in the pH of the consumption of the consumption of described organic solvent, the consumption of oxygenant, oxide catalyst, the consumption of phase-transfer catalyst, reaction, the temperature and time of reaction are all the same.
Without prejudice to the field on the basis of common sense, each preferred feature above-mentioned in the present invention can arbitrary combination, obtains the preferred embodiments of the invention.
In the present invention, the saturated C of described Lower alkyl groups mean linear or side chain
1~ C
7alkyl, as: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, 2-methyl-propyl, the tertiary butyl, n-pentyl and n-hexyl etc.
In the present invention, described lower alkoxy refers to that above-mentioned low alkyl group is connected with a Sauerstoffatom group of gained, as: methoxyl group, oxyethyl group and positive propoxy etc.
In the present invention, described lower alkyl amide refers to that above-mentioned low alkyl group is connected with a carbonyl group of gained, as: ethanoyl and propionyl etc.
In the present invention, described low alkyl group acyloxy refers to that lower alkyl amide is connected with a Sauerstoffatom group of gained.
In the present invention, described N-(lower alkyl amide) amido refers to that lower alkyl amide is connected with-NH-the group of gained, as:
deng.
In the present invention, described aryl acyloxy refers to that aroyl is connected with a Sauerstoffatom group of gained.
In the present invention, described aroyl refers to that aryl is connected with a carbonyl group of gained.
In the present invention, term " alkyl " refers to comprise the radical of saturated aliphatic alkyl having and specify carbonatoms object side chain and straight chain.Such as, at " C
1~ C
10alkyl " in be defined as the group being included in and there is in straight chain or branched structure 1,2,3,4,5,6,7,8,9 or 10 carbon atom; What term " alkoxyl group " expression was connected by oxo bridge has described carbonatoms object acyclic alkyl groups, and thus, " alkoxyl group " comprises the definition of above alkyl; Term " aryl " refer to any stable can up to the monocycle of 7 atoms or bicyclic carbocyclic in each ring, wherein at least one ring is aromatic nucleus, the example of above-mentioned aryl unit comprises phenyl, naphthyl, tetralyl, 2,3-indanyls, xenyl, phenanthryl, anthryl or acenaphthenyl.
Raw material described in the present invention or reagent except special instruction, all commercially.
Positive progressive effect of the present invention is: cheaper starting materials of the present invention is easy to get, reaction conditions gentle, environmental pollution is little, and feed stock conversion is high, is conducive to industrial mass production.
Embodiment
Further illustrate the present invention by embodiment below, but the present invention is not limited.
Raw material used in embodiment or reagent except special instruction, all commercially.
Room temperature described in embodiment all refers to 20 DEG C.
HPLC condition:
Waters C18 post, 150 × 4.6mm;
Column temperature: 30 DEG C;
Moving phase: acetonitrile: water: 10% phosphoric acid=400: 600: 1; Flow velocity: 1.0mL/min;
Determined wavelength: 254nm.
Embodiment 1
4.042g (19.5mmol) 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate; under stirring; 0.031g (0.2mmol, 0.01eq.) 2,2 is added in system; 6; 6-tetramethyl piperidine-1-oxyradical, more slowly drip the 10mL ethyl acetate solution of 1.526g (6.58mmol, 0.34eq.) TCCA; after adding, stirred at ambient temperature reacts 30 minutes.After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 3.888g.Calculating yield is 97.12%.Through HPLC qualification, learn that product is 2-(N-ethanoyl) methylamino-1-phenyl-1-acetone, HPLC purity is 99.5%.
Embodiment 2
4.501g (21.7mmol) 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL toluene; under stirring; 0.036g (0.23mmol, 0.01eq.) 2,2 is added in system; 6; 6-tetramethyl piperidine-1-oxyradical, more slowly drip the 10mL toluene solution of 1.543g (6.65mmol, 0.33eq.) TCCA; after adding, react 30 minutes in stirred at ambient temperature.After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 3.748g.Calculating yield is 84.08%.In reaction solution, the HPLC purity of product is 94.37%.
Embodiment 3
0.503g (2.4mmol) 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 10mL ethyl acetate; under stirring; 0.004g (0.02mmol, 0.01eq.) 2,2 is added in system; 6; 6-tetramethyl piperidine-1-oxyradical, more slowly drip the 5mL ethyl acetate solution of 0.188g (0.8mmol, 0.33eq.) TCCA; after adding, stirring reaction 30 minutes at 40 DEG C.After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 15mL, 15mL distilled water successively, concentrated.Obtain enriched material 0.483g.Calculating yield is 96.97%.The HPLC purity 98.2% of product in reaction solution.
Embodiment 4
1.255g (6.05mmol) 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 20mL propyl formate; under stirring; 0.010g (0.064mmol, 0.01eq.) 2,2 is added in system; 6; 6-tetramethyl piperidine-1-oxyradical, more slowly drip the 10mL ethyl acetate solution of 0.471g (2.02mmol, 0.33eq.) TCCA; after adding, react 1 hour in stirred at ambient temperature.After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 1.209g.Calculating yield is 97.2%.The HPLC purity 97.7% of product in reaction solution.
Embodiment 5
0.461g (2.2mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 10mL ethyl propionate; under stirring; 1.682g (2.42mmol is added successively in system; 1.1eq.) aqueous sodium hypochlorite solution, the 0.007g (0.02mmol, 0.01eq.) 2,2 of 10.83%; 6; 6-tetramethyl piperidine-1-oxyradical and 0.007g (0.02mmol, 0.01eq.) tetra-n-butyl ammonium bromide, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 15mL, 15mL distilled water successively, concentrated.Obtain enriched material 0.372g.Calculating yield is 81.5%.The HPLC purity 87.74% of product in reaction solution.
Embodiment 6
0.492g (2.0mmol) 2-(N-ethyl)-methylamino-1-(2-methyl)-phenyl-n-butyl alcohol is dissolved in 10mL hexanaphthene, under stirring, 0.153g (2.0mmol is added successively in system, 1eq.) Peracetic Acid, 0.007g (0.02mmol, 0.01eq.) 2,2,6,6-tetramethyl piperidine-1-oxyradical and 0.007g (0.02mmol, 0.01eq.) tetra-n-butyl ammonium bromide, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 15mL, 15mL distilled water successively, concentrated.Obtain enriched material 0.385g.Calculating yield is 79.0%.The HPLC purity 99.7% of product in reaction solution.
Embodiment 7
3.844g (18.5mmol) 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL trichloromethane; under stirring; 0.023g (0.19mmol) 2 is added in system; 2; 6,6-tetramethyl piperidine-1-oxyradical, more slowly drip the 10mL ethyl acetate solution of 7.192g (30.9mmol) TCCA; after adding, stirred at ambient temperature reacts 30 minutes.After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 3.677g.To calculate yield be 96.6%, HPLC purity is 99.2%.
Embodiment 8
4.151g (20.22mmol) 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL acetonitrile; under stirring; 0.032g (0.21mmol) 2 is added in system; 2; 6,6-tetramethyl piperidine-1-oxyradical, more slowly drip the 10mL ethyl acetate solution of 15.665g (67.4mmol) TCCA; after adding, stirred at ambient temperature reacts 30 minutes.After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 3.864g.To calculate yield be 94.0%, HPLC purity is 98.4%.
Embodiment 9
4.337g (21.13mmol; 1eq.) 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL N; dinethylformamide; under stirring; 0.045g (0.21mmol is added in system; 0.01eq.) 7; 7; 9,9-tetramethyl--Isosorbide-5-Nitrae-dioxa-8-azaspiro [4.5] decane-8-oxyradical; slowly drip 1.770g (7.18mmol again; 0.34eq.) the 10mL ethyl acetate solution of TCCA, after adding, stirred at ambient temperature reacts 30 minutes.After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 4.037g.To calculate yield be 94.0%, HPLC purity is 97.7%.
Embodiment 10
5.459g (26.34mmol) 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL ether; under stirring; 0.063g (0.26mmol is added in system; 0.01eq.) (R; S)-2-ethyl-7; 7; 9; 9-tetramethyl--1; 4-dioxa-8-azaspiro [4.5] decane-8-oxyradical, more slowly drip the 10mL ethyl acetate solution of 2.040g (8.78mmol, 0.34eq.) TCCA; after adding, stirred at ambient temperature reacts 30 minutes.After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 4.990g.To calculate yield be 92.3%, HPLC purity is 98.6%.
Embodiment 11
4.775g (23.04mmol) 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL methyl tertiary butyl ether; under stirring; 0.060g (0.23mmol is added in system; 0.01eq.) 3; 3; 8; 8; 10,10-vegolysen, 5-dioxa-9-azaspiro [5.5] undecane-9-oxyradical; slowly drip 1.785g (7.68mmol again; 0.34eq.) the 10mL ethyl acetate solution of TCCA, after adding, stirred at ambient temperature reacts 30 minutes.After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 4.284g.To calculate yield be 90.6%, HPLC purity is 99.3%.
Embodiment 12
5.248g (25.32mmol) 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate; under stirring; 0.050g (0.25mmol, 0.01eq.) 4-(kharophen)-2,2 is added in system; 6; 6-tetramethyl piperidine-1-oxyradical, more slowly drip the 10mL ethyl acetate solution of 1.961g (8.44mmol, 0.34eq.) TCCA; after adding, stirred at ambient temperature reacts 30 minutes.After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 3.701g.To calculate yield be 71.2%, HPLC purity is 98.4%.
Embodiment 13
15.01g (72.42mmol) 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate; under stirring; 0.003g (0.024mmol) 2 is added in system; 2; 6,6-tetramethyl piperidine-1-oxyradical, more slowly drip the 30mL ethyl acetate solution of 1.870g (8.045mmol) TCCA; after adding, stirred at ambient temperature reacts 30 minutes.After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 4.801g.Calculating yield is 96.9%.HPLC purity is 78.8%.
Embodiment 14
11.04g (53.25mmol) 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate; under stirring; 5.550g (35.5mmol) 2 is added in system; 2; 6,6-tetramethyl piperidine-1-oxyradical, more slowly drip the 30mL ethyl acetate solution of 1.375g (5.92mmol) TCCA; after adding, stirred at ambient temperature reacts 30 minutes.After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 3.597g.Calculating yield is 98.7%.HPLC purity is 98.4%.
Embodiment 15
4.988g (24.06mmol) 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate; under stirring; 0.041g (0.24mmol, 0.01eq.) 2,2 is added in system; 6; 6-tetramethyl piperidine-1-oxyradical, more slowly drip the 30mL ethyl acetate solution of 1.873g (8.03mmol, 0.34eq.) TCCA; after adding, stirring reaction 30 minutes at 0 DEG C.After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 4.806g.Calculating yield is 97.3%.HPLC purity is 99.6%.
Embodiment 16
4.769g (23.01mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate; under stirring; 17.407g (25.31mmol is added successively in system; 1.1eq.) aqueous sodium hypochlorite solution, the 0.041g (0.23mmol, 0.01eq.) 2,2 of 10.83%; 6; 6-tetramethyl piperidine-1-oxyradical and 0.008g (0.02mmol, 0.01eq.) PEG-400, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 4.085g.Calculating yield is 86.5%.The HPLC purity 98.5% of product in reaction solution.
Embodiment 17
5.013g (24.18mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL toluene; under stirring; 18.290g (25.31mmol is added successively in system; 1.1eq.) aqueous sodium hypochlorite solution, the 0.038g (0.24mmol, 0.01eq.) 2,2 of 10.83%; 6; 6-tetramethyl piperidine-1-oxyradical and 0.005g (0.02mmol, 0.01eq.) 18-are preced with-6, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 3.535g.Calculating yield is 71.2%.The HPLC purity 97.6% of product in reaction solution.
Embodiment 18
5.126g (24.73mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL hexanaphthene; under stirring; 18.690g (27.2mmol is added successively in system; 1.1eq.) aqueous sodium hypochlorite solution, the 0.039g (0.25mmol, 0.01eq.) 2,2 of 10.83%; 6; 6-tetramethyl piperidine-1-oxyradical and 0.008g (0.02mmol, 0.01eq.) Tetraphenylphosphonium Bromide, use saturated Na
2cO
3solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 3.535g.Calculating yield is 69.8%.The HPLC purity 88.6% of product in reaction solution.
Embodiment 19
5.071g (24.46mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL methylene dichloride; under stirring; 3.053g (26.9mmol is added successively in system; 1.1eq.) 30% hydrogen peroxide solution, 0.038g (0.24mmol; 0.01eq.) 2; 2; 6; 6-tetramethyl piperidine-1-oxyradical and 0.079g (0.245mmol; 0.01eq.) Tetrabutyl amonium bromide; with saturated NaOH solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 3.972g.Calculating yield is 79.1%.
Embodiment 20
4.993g (24.09mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL acetonitrile; under stirring; 3.023g (26.5mmol is added successively in system; 1.1eq.) permonosulphuric acid, 0.037g (0.24mmol, 0.01eq.) 2,2; 6; 6-tetramethyl piperidine-1-oxyradical and 0.078g (0.243mmol, 0.01eq.) Tetrabutyl amonium bromide, with saturated Ca (HCO
3)
2solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 3.911g.Calculating yield is 79.1%.
Embodiment 21
5.261g (25.4mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mLN; dinethylformamide; under stirring; 19.195g (27.92mmol is added successively in system; 1.1eq.) aqueous sodium hypochlorite solution, the 0.045g (0.21mmol of 10.83%; 0.01eq.) 7; 7; 9; 9-tetramethyl--1; 4-dioxa-8-azaspiro [4.5] decane-8-oxyradical and 0.008g (0.025mmol, 0.01eq.) tetra-n-butyl ammonium bromide, with saturated Ca (OH)
2solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 0.372g.Calculating yield is 83.6%.
Embodiment 22
4.876g (23.5mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mLN; N-N,N-DIMETHYLACETAMIDE; under stirring; 17.825g (25.92mmol is added successively in system; 1.1eq.) aqueous sodium hypochlorite solution, the 0.051g (0.21mmol of 10.83%; 0.01eq.) (R; S)-2-ethyl-7; 7; 9,9-tetramethyl--Isosorbide-5-Nitrae-dioxa-8-azaspiro [4.5] decane-8-oxyradical and 0.008g (0.024mmol; 0.01eq.) tetra-n-butyl ammonium bromide, uses saturated K
2cO
3solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 0.372g.Calculating yield is 89.7%.
Embodiment 23
4.934g (23.8mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL ether, under stirring, 18.009g (26.20mmol is added successively in system, 1.1eq.) the aqueous sodium hypochlorite solution of 10.83%, 0.059g (0.23mmol, 0.01eq.) 3, 3, 8, 8, 10, 10-vegolysen, 5-dioxa-9-azaspiro [5.5] undecane-9-oxyradical and 0.008g (0.024mmol, 0.01eq.) tetra-n-butyl ammonium bromide, with saturated KOH solution regulation system pH to 9.0 ~ 9.2, 1 hour is reacted in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 4.158g.Calculating yield is 85.1%.
Embodiment 24
4.859g (23.4mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL methyl tertiary butyl ether; under stirring; 17.734g (25.80mmol is added successively in system; 1.1eq.) aqueous sodium hypochlorite solution, the 0.048g (0.23mmol of 10.83%; 0.01eq.) 4-(kharophen)-2; 2; 6; 6-tetramethyl piperidine-1-oxyradical and 0.008g (0.024mmol; 0.01eq.) tetra-n-butyl ammonium bromide, uses saturated KHCO
3solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 3.724g.Calculating yield is 77.4%.
Embodiment 25
5.037g (24.30mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL tetracol phenixin; under stirring; 18.373g (26.73mmol is added successively in system; 1.1eq.) aqueous sodium hypochlorite solution, the 0.004g (0.026mmol, 0.001eq.) 2,2 of 10.83%; 6; 6-tetramethyl piperidine-1-oxyradical and 0.008g (0.024mmol, 0.01eq.) tetra-n-butyl ammonium bromide, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 4.031g.Calculating yield is 80.8%.
Embodiment 26
4.877g (23.53mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL n-butyl propionate; under stirring; 17.792g (25.88mmol is added successively in system; 1.1eq.) aqueous sodium hypochlorite solution, the 0.369g (0.26mmol, 0.1eq.) 2,2 of 10.83%; 6; 6-tetramethyl piperidine-1-oxyradical and 0.008g (0.024mmol, 0.01eq.) tetra-n-butyl ammonium bromide, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 4.313g.Calculating yield is 89.3%.
Embodiment 27
5.304g (25.59mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL propyl formate; under stirring; 19.349g (28.15mmol is added successively in system; 1.1eq.) aqueous sodium hypochlorite solution, the 0.037g (0.026mmol, 0.01eq.) 2,2 of 10.83%; 6; 6-tetramethyl piperidine-1-oxyradical and 0.084g (0.24mmol, 0.1eq.) tetra-n-butyl ammonium bromide, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 4.691g.Calculating yield is 89.3%.
Embodiment 28
5.284g (25.49mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate; under stirring; 19.276g (28.05mmol is added successively in system; 1.1eq.) aqueous sodium hypochlorite solution, the 0.037g (0.026mmol, 0.01eq.) 2,2 of 10.83%; 6; 6-tetramethyl piperidine-1-oxyradical and 0.001g (0.002mmol, 0.001eq.) tetra-n-butyl ammonium bromide, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, react 1 hour in stirred at ambient temperature.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 4.443g.Calculating yield is 84.9%.
Embodiment 29
5.079g (24.50mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate; under stirring; 18.55g (26.97mmol is added successively in system; 1.1eq.) aqueous sodium hypochlorite solution, the 0.037g (0.026mmol, 0.01eq.) 2,2 of 10.83%; 6; 6-tetramethyl piperidine-1-oxyradical and 0.008g (0.025mmol, 0.01eq.) tetra-n-butyl ammonium bromide, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 0 DEG C.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 3.058g.Calculating yield is 60.8%.
Embodiment 30
5.264g (25.39mmol) 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate; under stirring; 19.229g (27.97mmol is added successively in system; 1.1eq.) aqueous sodium hypochlorite solution, the 0.036g (0.026mmol, 0.01eq.) 2,2 of 10.83%; 6; 6-tetramethyl piperidine-1-oxyradical and 0.008g (0.025mmol, 0.01eq.) tetra-n-butyl ammonium bromide, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 40 DEG C.After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated.Obtain enriched material 3.050g.Calculating yield is 58.5%.
Claims (40)
1. such as formula a preparation method for the alpha-amino ketone derivative shown in II, it is characterized in that comprising the following step: in organic solvent, react such as formula the compound shown in I under the effect of TCCA (Trichloroisocyanuric acid), oxide catalyst; The temperature of described reaction is 10 ~ 40 DEG C;
Wherein, R
1for phenyl; R
2and R
3for methyl; R
4for ethanoyl;
Wherein, described oxide catalyst is for such as formula the compound shown in III:
Wherein, R
5and R
5' be methyl;
R
6and R
7it is all hydrogen atom; Or R
6and R
7one is hydrogen atom, and another is
or R
6and R
7together for the Ketal form shown in following formula a, formula b or formula c:
Wherein, R
8for ethyl;
R
9and R
9' be methyl;
Y is for the group form shown in following formula d, formula e or formula f:
Wherein, X
-for fluorion, chlorion, bromide anion or iodide ion.
2. the preparation method of compound ii as claimed in claim 1, it is characterized in that: described organic solvent is methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, pentyl acetate, methyl-formiate, ethyl formate, propyl formate, isopropyl formate, butyl formate, tetryl formate, pentyl formate, methyl propionate, ethyl propionate, propyl propionate, n-butyl propionate, isobutyl propionate, amyl propionate, benzene, toluene, hexanaphthene, methylene dichloride, trichloromethane, tetracol phenixin, 1, 2-ethylene dichloride, acetonitrile, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, one or more in ether and methyl tertiary butyl ether.
3. the preparation method of compound ii as claimed in claim 1, is characterized in that: described TCCA (Trichloroisocyanuric acid) and the mol ratio of chemical compounds I are 1:3 ~ 10:3.
4. the preparation method of compound ii as claimed in claim 1, is characterized in that: described oxide catalyst is 2,2,6,6-tetramethyl piperidine-1-oxyradical and/or 4-acetylaminohydroxyphenylarsonic acid 2,2,6,6-tetramethyl piperidine-1-oxyradical.
5. the preparation method of compound ii as claimed in claim 1, is characterized in that: described oxide catalyst and the mol ratio of chemical compounds I are 0.001:3 ~ 2:3.
6. the preparation method of compound ii as claimed in claim 1, is characterized in that: till time of described reaction completes with detection reaction.
7. the preparation method of compound ii as claimed in claim 1, is characterized in that:
4.042g 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate, under stirring, 0.031g 2 is added in system, 2,6,6-tetramethyl piperidine-1-oxyradical, then the 10mL ethyl acetate solution slowly dripping 1.526g TCCA (Trichloroisocyanuric acid), after adding, stirring reaction 30 minutes at 20 DEG C; After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated, obtain enriched material 3.888g.
8. the preparation method of compound ii as claimed in claim 1, is characterized in that:
4.501g 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL toluene, under stirring, 0.036g 2 is added in system, 2,6,6-tetramethyl piperidine-1-oxyradical, then the 10mL toluene solution slowly dripping 1.543g TCCA (Trichloroisocyanuric acid), after adding, stirring reaction 30 minutes at 20 DEG C; After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated, obtain enriched material 3.748g.
9. the preparation method of compound ii as claimed in claim 1, is characterized in that:
0.503g 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 10mL ethyl acetate, under stirring, adds 0.004g 2 in system; 2; 6,6-tetramethyl piperidine-1-oxyradical, then the 5mL ethyl acetate solution slowly dripping 0.188g TCCA (Trichloroisocyanuric acid); after adding; stirring reaction 30 minutes at 40 DEG C, after completion of the reaction, respectively washes twice with the saturated sodium bisulfite liquid of 15mL, 15mL distilled water successively; concentrated, obtain enriched material 0.483g.
10. the preparation method of compound ii as claimed in claim 1, is characterized in that:
1.255g 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 20mL propyl formate, under stirring, 0.010g 2 is added in system, 2,6,6-tetramethyl piperidine-1-oxyradical, then the 10mL ethyl acetate solution slowly dripping 0.471g TCCA (Trichloroisocyanuric acid), after adding, stirring reaction 1 hour at 20 DEG C; After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated, obtain enriched material 1.209g.
The preparation method of 11. compound iis as claimed in claim 1, is characterized in that:
3.844g 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL trichloromethane, under stirring, adds 0.023g 2 in system; 2; 6,6-tetramethyl piperidine-1-oxyradical, then the 10mL ethyl acetate solution slowly dripping 7.192g TCCA (Trichloroisocyanuric acid); after adding; stirring reaction 30 minutes at 20 DEG C, after completion of the reaction, respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively; concentrated, obtain enriched material 3.677g.
The preparation method of 12. compound iis as claimed in claim 1, is characterized in that:
4.151g 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL acetonitrile, under stirring, adds 0.032g 2 in system; 2; 6,6-tetramethyl piperidine-1-oxyradical, then the 10mL ethyl acetate solution slowly dripping 15.665g TCCA (Trichloroisocyanuric acid); after adding; stirring reaction 30 minutes at 20 DEG C, after completion of the reaction, respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively; concentrated, obtain enriched material 3.864g.
The preparation method of 13. compound iis as claimed in claim 1, is characterized in that:
4.337g 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL N; dinethylformamide; under stirring; 0.045g 7 is added in system; 7; 9; 9-tetramethyl--Isosorbide-5-Nitrae-dioxa-8-azaspiro [4.5] decane-8-oxyradical, then the 10mL ethyl acetate solution slowly dripping 1.770g TCCA (Trichloroisocyanuric acid); after adding; stirring reaction 30 minutes at 20 DEG C, after completion of the reaction, respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively; concentrated, obtain enriched material 4.037g.
The preparation method of 14. compound iis as claimed in claim 1, is characterized in that:
5.459g 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL ether, under stirring, 0.063g (R, S)-2-ethyl-7,7 is added in system, 9,9-tetramethyl--Isosorbide-5-Nitrae-dioxa-8-azaspiro [4.5] decane-8-oxyradical, then the 10mL ethyl acetate solution slowly dripping 2.040g TCCA (Trichloroisocyanuric acid), after adding, stirring reaction 30 minutes at 20 DEG C; After completion of the reaction, respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated, obtain enriched material 4.990g.
The preparation method of 15. compound iis as claimed in claim 1, is characterized in that:
4.775g 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL methyl tertiary butyl ether; under stirring; 0.060g 3 is added in system; 3; 8; 8,10,10-vegolysen; 5-dioxa-9-azaspiro [5.5] undecane-9-oxyradical; slowly drip the 10mL ethyl acetate solution of 1.785g TCCA (Trichloroisocyanuric acid) again, after adding, stirring reaction 30 minutes at 20 DEG C; after completion of the reaction; respectively wash twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated, obtain enriched material 4.284g.
The preparation method of 16. compound iis as claimed in claim 1, is characterized in that:
5.248g 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate, under stirring, adds 0.050g 4-(kharophen)-2 in system; 2; 6,6-tetramethyl piperidine-1-oxyradical, then the 10mL ethyl acetate solution slowly dripping 1.961g TCCA (Trichloroisocyanuric acid); after adding; stirring reaction 30 minutes at 20 DEG C, after completion of the reaction, respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively; concentrated, obtain enriched material 3.701g.
The preparation method of 17. compound iis as claimed in claim 1, is characterized in that:
15.01g 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate, under stirring, adds 0.003g 2 in system; 2; 6,6-tetramethyl piperidine-1-oxyradical, then the 30mL ethyl acetate solution slowly dripping 1.870g TCCA (Trichloroisocyanuric acid); after adding; stirring reaction 30 minutes at 20 DEG C, after completion of the reaction, respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively; concentrated, obtain enriched material 4.801g.
The preparation method of 18. compound iis as claimed in claim 1, is characterized in that:
11.04g 2-(N-ethanoyl) methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate, under stirring, adds 5.550g 2 in system; 2; 6,6-tetramethyl piperidine-1-oxyradical, then the 30mL ethyl acetate solution slowly dripping 1.375g TCCA (Trichloroisocyanuric acid); after adding; stirring reaction 30 minutes at 20 DEG C, after completion of the reaction, respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively; concentrated, obtain enriched material 3.597g.
19. 1 kinds of preparation methods such as formula the alpha-amino ketone derivative shown in II, it is characterized in that comprising the following step: in organic solvent, be under the condition of 8 ~ 11 at pH, react such as formula the compound shown in I under the effect of oxygenant, oxide catalyst, pH adjusting agent and phase-transfer catalyst; The temperature of described reaction is 10 ~ 20 DEG C;
Wherein, R
1for phenyl; R
2and R
3for methyl; R
4for ethanoyl;
Wherein, described oxide catalyst is for such as formula the compound shown in III:
Wherein, R
5and R
5' be methyl;
R
6and R
7it is all hydrogen atom; Or R
6and R
7one is hydrogen atom, and another is
or R
6and R
7together for the Ketal form shown in following formula a, formula b or formula c:
Wherein, R
8for ethyl;
R
9and R
9' be methyl;
Y is for the group form shown in following formula d, formula e or formula f:
Wherein, X
-for fluorion, chlorion, bromide anion or iodide ion;
Wherein, described oxygenant is one or more in hydrogen peroxide, clorox, hypochlorous acid, peracid and persalt; Described phase-transfer catalyst is polyoxyethylene glycol and/or quaternary ammonium salt.
The preparation method of 20. compound iis as claimed in claim 19, it is characterized in that: described organic solvent is methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, pentyl acetate, methyl-formiate, ethyl formate, propyl formate, isopropyl formate, butyl formate, tetryl formate, pentyl formate, methyl propionate, ethyl propionate, propyl propionate, n-butyl propionate, isobutyl propionate, amyl propionate, benzene, toluene, hexanaphthene, methylene dichloride, trichloromethane, tetracol phenixin, 1, 2-ethylene dichloride, acetonitrile, N, dinethylformamide, N, N-N,N-DIMETHYLACETAMIDE, one or more in ether and methyl tertiary butyl ether.
The preparation method of 21. compound iis as claimed in claim 19, is characterized in that: described peracid is permonosulphuric acid, peroxy-disulfuric acid, peracetic acid, cross valeric acid, cross in isovaleric acid, peroxyformic acid, Peracetic Acid, peroxy trifluoroacetic acid, Perpropionic Acid, Perbutyric Acid, peroxide isovaleric acid, benzoyl hydroperoxide, metachloroperbenzoic acid, nitroperoxybenzoic and monoperphthalic acid one or more; Described persalt is peroxy-monosulfate and/or peroxydisulfate.
The preparation method of 22. compound iis as claimed in claim 19: it is characterized in that: described oxygenant and the mol ratio of chemical compounds I are 1:1 ~ 1.2:1.
The preparation method of 23. compound iis as claimed in claim 19, is characterized in that: described pH adjusting agent is NaHCO
3, Na
2cO
3, NaOH, KHCO
3, K
2cO
3, KOH, Ca (HCO
3)
2with Ca (OH)
2in one or more.
The preparation method of 24. compound iis as claimed in claim 19, is characterized in that: described oxide catalyst is 2,2,6,6-tetramethyl piperidine-1-oxyradical and/or 4-acetylaminohydroxyphenylarsonic acid 2,2,6,6-tetramethyl piperidine-1-oxyradical.
The preparation method of 25. compound iis as claimed in claim 19, is characterized in that: described oxide catalyst and the mol ratio of chemical compounds I are 0.001:1 ~ 0.1:1.
The preparation method of 26. compound iis as claimed in claim 19, is characterized in that: described polyoxyethylene glycol is PEG-200 and/or PEG-400, described quaternary ammonium salt is methyl triethyl ammonium chloride, methyl triethylammonium bromide, benzyl trimethyl ammonium chloride, benzyltrimethylammonium bromide, benzyltrimethylammonium hydroxide, benzyltriethylammoinium chloride, benzyl triethyl ammonium bromide, tetramethyl ammonium chloride, 4 bromide, Tetramethylammonium iodide, Tetramethylammonium hydroxide, tetramethyl-monoammonium sulfate, tetrabutylammonium chloride, Tetrabutyl amonium bromide, tetrabutylammonium iodide, TBAH, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, one or more in Dodecyl trimethyl ammonium chloride and tetradecyl trimethyl ammonium chloride.
The preparation method of 27. compound iis as claimed in claim 19, is characterized in that: described phase-transfer catalyst and the mol ratio of chemical compounds I are 0.001:1 ~ 0.1:1.
The preparation method of 28. compound iis as claimed in claim 19, is characterized in that: till time of described reaction completes with detection reaction.
The preparation method of 29. compound iis as claimed in claim 19, is characterized in that:
0.461g 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 10mL ethyl propionate; under stirring; the aqueous sodium hypochlorite solution of 1.682g 10.83%, 0.007g 2 is added successively in system; 2; 6; 6-tetramethyl piperidine-1-oxyradical and 0.007g tetra-n-butyl ammonium bromide, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 20 DEG C; After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 15mL, 15mL distilled water successively, concentrated; Obtain enriched material 0.372g.
The preparation method of 30. compound iis as claimed in claim 19, is characterized in that:
4.769g 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate; under stirring; the aqueous sodium hypochlorite solution of 17.407g 10.83%, 0.041g 2 is added successively in system; 2; 6; 6-tetramethyl piperidine-1-oxyradical and 0.008g PEG-400, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 20 DEG C, after completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated, obtains enriched material 4.085g.
The preparation method of 31. compound iis as claimed in claim 19, is characterized in that:
5.071g 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL methylene dichloride, under stirring, 3.053g 30% hydrogen peroxide solution, 0.038g 2 is added successively in system, 2,6,6-tetramethyl piperidine-1-oxyradical and 0.079g Tetrabutyl amonium bromide, with saturated NaOH solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 20 DEG C; After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated; Obtain enriched material 3.972g.
The preparation method of 32. compound iis as claimed in claim 19, is characterized in that:
4.993g 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL acetonitrile, under stirring, adds 3.023g permonosulphuric acid, 0.037g 2 in system successively; 2; 6,6-tetramethyl piperidine-1-oxyradical and 0.078g Tetrabutyl amonium bromide, with saturated Ca (HCO
3)
2solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 20 DEG C; After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated; Obtain enriched material 3.911g.
The preparation method of 33. compound iis as claimed in claim 19, is characterized in that:
5.261g 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL N; dinethylformamide; under stirring; aqueous sodium hypochlorite solution, the 0.045g7 of 19.195g 10.83% is added successively in system; 7,9,9-tetramethyl--1; 4-dioxa-8-azaspiro [4.5] decane-8-oxyradical and 0.008g tetra-n-butyl ammonium bromide, with saturated Ca (OH)
2solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 20 DEG C; After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated; Obtain enriched material 0.372g.
The preparation method of 34. compound iis as claimed in claim 19, is characterized in that:
4.876g 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mLN; N-N,N-DIMETHYLACETAMIDE; under stirring; the aqueous sodium hypochlorite solution of 17.825g 10.83%, 0.051g (R, S)-2-ethyl-7,7 is added successively in system; 9; 9-tetramethyl--Isosorbide-5-Nitrae-dioxa-8-azaspiro [4.5] decane-8-oxyradical and 0.008g tetra-n-butyl ammonium bromide, use saturated K
2cO
3solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 20 DEG C; After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated; Obtain enriched material 0.372g.
The preparation method of 35. compound iis as claimed in claim 19, is characterized in that:
4.934g 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL ether, under stirring, the aqueous sodium hypochlorite solution of 18.009g 10.83%, 0.059g 3,3,8 is added successively in system, 8,10,10-vegolysen, 5-dioxa-9-azaspiro [5.5] undecane-9-oxyradical and 0.008g tetra-n-butyl ammonium bromide, with saturated KOH solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 20 DEG C; After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated; Obtain enriched material 4.158g.
The preparation method of 36. compound iis as claimed in claim 19, is characterized in that:
4.859g 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL methyl tertiary butyl ether; under stirring; the aqueous sodium hypochlorite solution of 17.734g 10.83%, 0.048g 4-(kharophen)-2 is added successively in system; 2; 6; 6-tetramethyl piperidine-1-oxyradical and 0.008g tetra-n-butyl ammonium bromide, use saturated KHCO
3solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 20 DEG C; After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated; Obtain enriched material 3.724g.
The preparation method of 37. compound iis as claimed in claim 19, is characterized in that:
5.037g 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL tetracol phenixin; under stirring; the aqueous sodium hypochlorite solution of 18.373g 10.83%, 0.004g 2 is added successively in system; 2; 6; 6-tetramethyl piperidine-1-oxyradical and 0.008g tetra-n-butyl ammonium bromide, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 20 DEG C; After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated; Obtain enriched material 4.031g.
The preparation method of 38. compound iis as claimed in claim 19, is characterized in that:
4.877g 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL n-butyl propionate; under stirring; the aqueous sodium hypochlorite solution of 17.792g 10.83%, 0.369g 2 is added successively in system; 2; 6; 6-tetramethyl piperidine-1-oxyradical and 0.008g tetra-n-butyl ammonium bromide, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 20 DEG C; After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated; Obtain enriched material 4.313g.
The preparation method of 39. compound iis as claimed in claim 19, is characterized in that:
5.304g 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL propyl formate; under stirring; the aqueous sodium hypochlorite solution of 19.349g 10.83%, 0.037g 2 is added successively in system; 2; 6; 6-tetramethyl piperidine-1-oxyradical and 0.084g tetra-n-butyl ammonium bromide, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 20 DEG C; After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated; Obtain enriched material 4.691g.
The preparation method of 40. compound iis as claimed in claim 19, is characterized in that:
5.284g 2-(N-ethanoyl)-methylamino-1-phenyl-1-propanol is dissolved in 30mL ethyl acetate; under stirring; the aqueous sodium hypochlorite solution of 19.276g 10.83%, 0.037g 2 is added successively in system; 2; 6; 6-tetramethyl piperidine-1-oxyradical and 0.001g tetra-n-butyl ammonium bromide, use saturated NaHCO
3solution regulation system pH to 9.0 ~ 9.2, stirring reaction 1 hour at 20 DEG C; After completion of the reaction, extracting and separating, organic phase respectively washes twice with the saturated sodium bisulfite liquid of 30mL, 30mL distilled water successively, concentrated; Obtain enriched material 4.443g.
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| CN111170926B (en) * | 2020-01-10 | 2022-02-15 | 浙江工业大学 | Method for catalyzing asymmetric synthesis of chiral beta-alkynyl-beta-aminoketone derivative |
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| CN1156713A (en) * | 1995-11-21 | 1997-08-13 | 弗·哈夫曼-拉罗切有限公司 | Process for oxidation of primary or secondary alcohols |
| CN101747313A (en) * | 2008-12-11 | 2010-06-23 | 上海医药工业研究院 | Preparation method of (3R, 5S)-3,5-dyhydroxy-6-oxo-caproate derivative |
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| CN1156713A (en) * | 1995-11-21 | 1997-08-13 | 弗·哈夫曼-拉罗切有限公司 | Process for oxidation of primary or secondary alcohols |
| CN101747313A (en) * | 2008-12-11 | 2010-06-23 | 上海医药工业研究院 | Preparation method of (3R, 5S)-3,5-dyhydroxy-6-oxo-caproate derivative |
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