CN102020615B - Morpholone derivative and preparation method thereof - Google Patents
Morpholone derivative and preparation method thereof Download PDFInfo
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- CN102020615B CN102020615B CN200910092933A CN200910092933A CN102020615B CN 102020615 B CN102020615 B CN 102020615B CN 200910092933 A CN200910092933 A CN 200910092933A CN 200910092933 A CN200910092933 A CN 200910092933A CN 102020615 B CN102020615 B CN 102020615B
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Abstract
The invention relates to a morpholone derivative, which has a structure expressed by a formula I. The invention also relates to a preparation method for the morpholone derivative. The morpholone derivative can be used for providing a new choice for preparing 5,6-dihydro-8H-imidazo [2,1-c] [1,4] oxazine-2-formaldehyde. The morpholone derivative has simple structure and high selectivity and is easy to prepare; when the 5,6-dihydro-8H-imidazo [2,1-c] [1,4] oxazine-2-formaldehyde is prepared, 3-aldehyde isomers are not produced, separation and purification are simple, and the product purity is high, and the cost of the whole process route for preparing the 5,6-dihydro-8H-imidazo [2,1-c] [1,4] oxazine-2-formaldehyde by using the morpholone derivative is greatly reduced.
Description
Technical field
The present invention relates to chemical field, particularly, the present invention relates to a kind of morpholone mai verivate and preparation method thereof.
Background technology
The compound of being represented by formula II is a kind of methylal penem, and it is that heterocycle passes through ethylene linkage and forms with being connected of penem 6-position carbon.Reference 1 (Antimicrob AgentsChemother, 2004,48 (12): the 4589-4596 page or leaf) disclose the comparison that presses down enzymic activity that this compound and Tazobactam Sodium carry out A group, B group and C group β-Nei Xiananmei etc.The result shows, the compound of being represented by formula II all has the good restraining effect to A group enzyme, its specific activity Tazobactam Sodium active strong 100～200 times; C group enzyme is also demonstrated stronger restraining effect, its specific activity Tazobactam Sodium active strong 15000～56000 times.
The synthetic of being represented by formula II of compound is through 5; 6-dihydro-8H-imidazoles [2,1-c] [1,4] oxazine-2-formaldehyde (compound of representing by formula III) and 4-nitrobenzyl-(5R; 6S)-6-bromine penem-3-ester under lewis acidic catalysis, carry out Aldol reaction and preparation (for example referring to Biochemistry; 2003,42 (45), the 13152-13159 page or leaf).But in disclosed compound method; 5,6-dihydro-8H-imidazoles [2,1-c] [1; 4] oxazine-2-formaldehyde has only the compound method of patent documentation US20040132708 and WO 2006130588 reports as the key intermediate that synthesizes the compound of being represented by formula II.This method prepares 3-thiomorpholine ketone by the 3-morpholone mai; The process methyl iodide methylates again, ammonium chloride ammonia is separated and make 5 with 2-bromo-3-hydroxyl acrolein reaction; 6-dihydro-8H-imidazoles [2; 1-c] [1,4] oxazine-2-formaldehyde and 3 aldehyde radical mixture of isomers thereof separate obtaining target compound then through silica gel column chromatography.This preparing method's yield is low, purification difficult, and the technology cost is high, in actual production, has wretched insufficiency, therefore can't carry out suitability for industrialized production.
Summary of the invention
The purpose of this invention is to provide a kind of novel morpholone mai verivate.
The present invention also aims to provide the preparation method of this novel morpholone mai verivate.
In order to realize the object of the invention, the present invention provides a kind of morpholone mai verivate, and it has the structure of being represented by formula I (hereinafter being called 2-(3-oxo morpholinyl) ethanamide again)
The present invention also provides the preparation method of this morpholone mai verivate, and this method comprises: make 3-morpholone mai and Haloacetamide in solvent, in the presence of alkali, react according to following route, thereby generate the morpholone mai verivate of representing by formula I,
Wherein X is a chlorine or bromine.
In method of the present invention, the molar ratio of 3-morpholone mai, Haloacetamide and said alkali is preferably 1: (1～2): (1～3), the reaction times is preferably 0.5～48 hour.More preferably, the molar ratio of 3-morpholone mai, Haloacetamide and said alkali is 1: (1～1.5): (1～2), the reaction times is 12～24 hours.
Wherein, the 3-morpholone mai is a raw material commonly used in the chemical field, and it can be commercially available (for example can available from Ningbo ltd of pharmaceutical chemistry institute of high section); Also can be voluntarily synthetic (for example referring to J.Wuhan Univ. (Nat.Sci.Ed.) 2004; 50, (2), 173-176 page or leaf; Journal of Polymer Science, Part A Polymer Chemistry 2002,40, (24), 4550-4555 page or leaf; US 5349045 etc.).Haloacetamide (for example chlor(o)acetamide or bromoacetamide) also is commercially available, for example can be available from Ningbo ltd of pharmaceutical chemistry institute of high section.
In method of the present invention, temperature of reaction is preferably-80 ℃ to reflux temperature.Wherein " reflux temperature " is term well-known to those skilled in the art, and it typically refers to the temperature that under normal pressure, produces in the reaction system when refluxing.
In method of the present invention, said alkali is mineral alkali or organic bases.Wherein, Said alkali is preferably sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, calcium hydroxide, sodium methylate, sodium ethylate, sodium isopropylate, potassium isopropoxide, sodium tert-butoxide, potassium tert.-butoxide, sodium tert-amyl alcohol, tertiary amyl alcohol potassium, sodium hydrogencarbonate, saleratus, yellow soda ash, salt of wormwood, cesium carbonate, Quilonum Retard, sodium hydrogen, triethylamine, diisopropyl ethyl amine, tri-n-butylamine, pyridine or 2,6-lutidine.More preferably, said alkali is sodium hydroxide, Pottasium Hydroxide or sodium methylate.
In method of the present invention, said solvent is not participated in reaction, and it plays the effect of reaction medium.Wherein, Said solvent is preferably water, acetonitrile, methyl alcohol, ethanol, Virahol, sec-butyl alcohol, the trimethyl carbinol, 3-amylalcohol, 2-amylalcohol, tertiary amyl alcohol, 2-methyl-butanols, 3-methyl-3-amylalcohol, terepthaloyl moietie, ethylene glycol monomethyl ether, glycol dimethyl ether, glycerine, N; Dinethylformamide, N; N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, DMSO 99.8MIN., ETHYLE ACETATE, normal hexane, normal heptane, ether, sherwood oil, chloroform, methylene dichloride, THF, 2-methyltetrahydrofuran, 1,4-dioxane, benzene,toluene,xylene, sym-trimethylbenzene, chlorobenzene, dichlorobenzene or t-butyl methyl ether.More preferably, said solvent is water, ethanol, THF, 1,4-dioxane or toluene.
Selectively, after the reaction of the compound that above-mentioned preparation is represented by formula I finishes, can separate purification to it.Said separation purification step comprises: (1) is heated up and is steamed solvent; (2) add entry and with pH regulator agent (for example hydrochloric acid) with pH regulator to neutrality (for example 7); (3) extraction and collected organic layer; And (4) recrystallization.
For example, after reaction finished, heating up steamed solvent; Under ice bath, adding volume is the water of 5～10 times of remaining mixture volumes, transfers pH=7 with concentrated hydrochloric acid (37 massfraction %), with the methylene dichloride or the ethyl acetate extraction of 2～10 times of (volume) water yields; Triplicate separates obtaining organic layer.Organic layer is used anhydrous sodium sulfate drying, filters, and is evaporated to driedly, obtains bullion.Add dissolution with solvents, room temperature or be cooled to-80 ℃～25 ℃ recrystallizations 1～48 hour is filtered, and the crystal oven dry that obtains promptly makes 2-(3-oxo morpholinyl) ethanamide.Said dissolving can be water, acetonitrile, methyl alcohol, ethanol, Virahol, sec-butyl alcohol, the trimethyl carbinol, 3-amylalcohol, 2-amylalcohol, tertiary amyl alcohol, 2-methyl-butanols, 3-methyl-3-amylalcohol, terepthaloyl moietie, ethylene glycol monomethyl ether, glycol dimethyl ether, glycerine, N with solvent; Dinethylformamide, N; N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, DMSO 99.8MIN., ETHYLE ACETATE, normal hexane, normal heptane, ether, sherwood oil, chloroform, methylene dichloride, THF, 2-methyltetrahydrofuran, 1,4-dioxane, benzene,toluene,xylene, sym-trimethylbenzene, chlorobenzene, dichlorobenzene or t-butyl methyl ether.
In order to overcome deficiency of the prior art, the invention provides and a kind ofly can be used for preparing 5,6-dihydro-8H-imidazoles [2,1-c] [the novel morpholone mai verivate of 1,4] oxazine-2-formaldehyde.Because this morpholone mai derivant structure is simple, preparation easily, selectivity is high, and prepares 5; 6-dihydro-8H-imidazoles [2,1-c] [does not have 3 aldehyde radical isomer during 1,4] oxazine-2-formaldehyde; Separation and purification is simple, and product purity is high, therefore makes from this morpholone mai verivate preparation 5; [cost of the whole operational path of 1,4] oxazine-2-formaldehyde reduces 6-dihydro-8H-imidazoles [2,1-c] greatly.
Embodiment
Below description through embodiment the present invention is described further; But this is not to be limitation of the present invention; Those skilled in the art are according to basic thought of the present invention; Can make various modifications or improvement, but only otherwise break away from basic thought of the present invention, all within scope of the present invention.
Hereinafter, 3-morpholone mai, chlor(o)acetamide, bromoacetamide and ethylmagnesium bromide are available from Ningbo ltd of pharmaceutical chemistry institute of high section, and other solvents and reagent are available from Sigma company.
The preparation of embodiment 1:2-(3-oxo morpholinyl) ethanamide
At room temperature restrain 3-morpholone mais and 9.3 gram chlor(o)acetamides and 6.8 gram sodium ethylates and join in 120 milliliters of ethanol, be heated to 40 ℃, reacted 24 hours 10.1.Reaction steams ethanol after finishing, and reaction solution is chilled to room temperature, under the ice bath cooling, adds 50 ml waters, transfers pH=7 with concentrated hydrochloric acid (37 massfraction %), and with 100 milliliters dichloromethane extraction, triplicate separates obtaining organic layer.Organic layer is used anhydrous sodium sulfate drying, filters, and is evaporated to driedly, obtains bullion.Add 200 milliliters of ethanol and carry out recrystallization, recrystallization temperature is-10 ℃, and crystallization time is 24 hours.Filter,, promptly make 13.4 gram 2-(3-oxo morpholinyl) ethanamides, yield 85% the solid oven dry that obtains.
Structural formula is following:
Molecular formula: C
6H
10N
2O
3
Molecular weight: 158.16
Proterties: white solid
Nucleus magnetic resonance and mass-spectrometric data are following:
1H?NMR(500MHz，CDCl
3)：δ7.39(s，1H)，7.06(s，1H)，4.04(s，2H)，3.90(s，2H)，3.83(t，J＝5.0Hz，2H)，3.36(t，J＝5.0Hz，2H)；
13C?NMR(125MHz，CDCl
3)：δ169.4，166.3，67.3，63.1，48.1，47.1；
MS(API-ES)：(m/z)＝159(M+1)。
The preparation of embodiment 2:2-(3-oxo morpholinyl) ethanamide
At room temperature restrain 3-morpholone mais and 27.6 gram bromoacetamides and 20.4 gram sodium methylates and join in 150 milliliters of THFs, be heated to 70 ℃, reacted 0.5 hour 10.1.Reaction steams THF after finishing, and reaction solution is chilled to room temperature, under the ice bath cooling, adds 50 ml waters, transfers pH=7 with concentrated hydrochloric acid (37 massfraction %), and with 100 milliliters ethyl acetate extraction, triplicate separates obtaining organic layer.Organic layer is used anhydrous sodium sulfate drying, filters, and is evaporated to driedly, obtains bullion.Add 200 milliliters of toluene and carry out recrystallization, recrystallization temperature is-30 ℃, and crystallization time is 48 hours.Filter,, promptly make 14.5 gram 2-(3-oxo morpholinyl) ethanamides, yield 92% the solid oven dry that obtains.
Structural formula is following:
Molecular formula: C
6H
10N
2O
3
Molecular weight: 158.16
Proterties: white solid
Nucleus magnetic resonance and mass-spectrometric data are following:
1H?NMR(500MHz，CDCl
3)：δ7.39(s，1H)，7.06(s，1H)，4.04(s，2H)，3.90(s，2H)，3.83(t，J＝5.0Hz，2H)，3.36(t，J＝5.0Hz，2H)；
13C?NMR(125MHz，CDCl
3)：δ169.4，166.3，67.3，63.1，48.1，47.1；
MS(API-ES)：(m/z)＝159(M+1)。
The preparation of embodiment 3:2-(3-oxo morpholinyl) ethanamide
At room temperature restrain 3-morpholone mais and 14 gram chlor(o)acetamides and 8 gram sodium hydroxide and join in 150 milliliters of toluene, reacted 48 hours down at-78 ℃ with 10.1.Reaction steams toluene after finishing, and reaction solution is chilled to room temperature, under the ice bath cooling, adds 50 ml waters, transfers pH=7 with concentrated hydrochloric acid (37 massfraction %), and with 100 milliliters ethyl acetate extraction, triplicate separates obtaining organic layer.Organic layer is used anhydrous sodium sulfate drying, filters, and is evaporated to driedly, obtains bullion.Add 200 milliliters of toluene and carry out recrystallization, recrystallization temperature is-30 ℃, and crystallization time is 48 hours.Filter,, promptly make 14 gram 2-(3-oxo morpholinyl) ethanamides, yield 89% the solid oven dry that obtains.
Structural formula is following:
Molecular formula: C
6H
10N
2O
3
Molecular weight: 158.16
Proterties: white solid
Nucleus magnetic resonance and mass-spectrometric data are following:
1H?NMR(500MHz，CDCl
3)：δ7.39(s，1H)，7.06(s，1H)，4.04(s，2H)，3.90(s，2H)，3.83(t，J＝5.0Hz，2H)，3.36(t，J＝5.0Hz，2H)；
13C?NMR(125MHz，CDCl
3)：δ169.4，166.3，67.3，63.1，48.1，47.1；
MS(API-ES)：(m/z)＝159(M+1)。
The preparation of embodiment 4:2-(3-oxo morpholinyl) ethanamide
At room temperature restrain 3-morpholone mais and 14 gram chlor(o)acetamides and 14 gram Pottasium Hydroxide and join in 150 milliliters of toluene, reacted 12 hours down at 0 ℃ with 10.1.Reaction steams toluene after finishing, and reaction solution is chilled to room temperature, under the ice bath cooling, adds 50 ml waters, transfers pH=7 with concentrated hydrochloric acid (37 massfraction %), and with 100 milliliters ethyl acetate extraction, triplicate separates obtaining organic layer.Organic layer is used anhydrous sodium sulfate drying, filters, and is evaporated to driedly, obtains bullion.Add 200 milliliters of toluene and carry out recrystallization, recrystallization temperature is-30 ℃, and crystallization time is 48 hours.Filter,, promptly make 13.8 gram 2-(3-oxo morpholinyl) ethanamides, yield 88% the solid oven dry that obtains.
Structural formula is following:
Molecular formula: C
6H
10N
2O
3
Molecular weight: 158.16
Proterties: white solid
Nucleus magnetic resonance and mass-spectrometric data are following:
1H?NMR(500MHz，CDCl
3)：δ7.39(s，1H)，7.06(s，1H)，4.04(s，2H)，3.90(s，2H)，3.83(t，J＝5.0Hz，2H)，3.36(t，J＝5.0Hz，2H)；
13C?NMR(125MHz，CDCl
3)：δ169.4，166.3，67.3，63.1，48.1，47.1；
MS(API-ES)：(m/z)＝159(M+1)。
The preparation of embodiment 5:2-(3-oxo morpholinyl) ethanamide
At room temperature restrain 3-morpholone mais and 14 gram chlor(o)acetamides and 14 gram Pottasium Hydroxide and join in 150 milliliters of toluene, be heated to backflow, reacted 6 hours 10.1.Reaction steams toluene after finishing, and reaction solution is chilled to room temperature, under the ice bath cooling, adds 50 ml waters, transfers pH=7 with concentrated hydrochloric acid (37 massfraction %), and with 100 milliliters ethyl acetate extraction, triplicate separates obtaining organic layer.Organic layer is used anhydrous sodium sulfate drying, filters, and is evaporated to driedly, obtains bullion.Add 200 milliliters of toluene and carry out recrystallization, recrystallization temperature is-30 ℃, and crystallization time is 48 hours.Filter,, promptly make 13.6 gram 2-(3-oxo morpholinyl) ethanamides, yield 87% the solid oven dry that obtains.
Structural formula is following:
Molecular formula: C
6H
10N
2O
3
Molecular weight: 158.16
Proterties: white solid
Nucleus magnetic resonance and mass-spectrometric data are following:
1H?NMR(500MHz，CDCl
3)：δ7.39(s，1H)，7.06(s，1H)，4.04(s，2H)，3.90(s，2H)，3.83(t，J＝5.0Hz，2H)，3.36(t，J＝5.0Hz，2H)；
13C?NMR(125MHz，CDCl
3)：δ169.4，166.3，67.3，63.1，48.1，47.1；
MS(API-ES)：(m/z)＝159(M+1)。
Embodiment 6:2-chloro-6,8-dihydro-5H-imidazoles [2, the 1-c]-[preparation of 1,4] oxazine
At room temperature, 2-(the 3-oxo morpholinyl) ethanamide that 15.8 grams are made among the embodiment 1 restrains POCl3s with 30.7 and 200 milliliters of toluene are put in the reaction kettle, is heated to 100 ℃, reacts 48 hours.Reaction steams toluene and POCl3 after finishing, and residuum is chilled to room temperature.Under ice bath, add 50 ml waters, transfer pH=9 with 10 weight % aqueous sodium hydroxide solutions, with 100 milliliters of ethyl acetate extractions, triplicate separates obtaining organic layer.Organic layer is used anhydrous sodium sulfate drying, filters, and concentrating under reduced pressure promptly gets 1.9 gram 2-chloro-6,8-dihydro-5H-imidazoles [2,1-c]-[1,4] oxazine, yield 12%.
Structural formula is following:
Molecular formula: C
6H
7ClN
2O
Molecular weight: 158.59
Proterties: white solid
Fusing point: 81-82 ℃
Nucleus magnetic resonance and mass-spectrometric data are following:
1H?NMR(400MHz，CDCl
3)：δ6.76(s，1H)，4.76(s，2H)，4.05(t，J＝4.5Hz，2H)，3.98(t，J＝5.1Hz，2H)；
13C?NMR(100MHz，CDCl
3)：δ140.4，129.2，113.4，64.6，63.7，43.9；
MS(EI)：(m/z)＝158(M
+)。
Embodiment 7:5,6-dihydro-8H-imidazoles [2, the 1-c] [preparation of 1,4] oxazine-2-formaldehyde
Under room temperature, nitrogen protection, with the 2-chloro-6 that makes among the 15.8 gram embodiment 6,8-dihydro-5H-imidazoles [2,1-c]-[1,4] oxazine adds in 100 milliliters of ether that contain 14.6 gram ethylmagnesium bromide, back flow reaction 6 hours.After reaction finishes, under ice bath, restrain anhydrous N, dinethylformamide, back flow reaction 24 hours to wherein adding 35.Afterwards, decompression steams ether, under ice bath, regulates pH=7 with saturated ammonium chloride solution; With 100 milliliters of ethyl acetate extractions, triplicate separates obtaining organic layer.Organic layer is used anhydrous sodium sulfate drying, filters, and is evaporated to driedly, obtains bullion; Add 100 milliliters of toluene ,-20 ℃ of recrystallizations 12 hours filter the crystal oven dry that obtains and promptly make 10.6 grams 5,6-dihydro-8H-imidazoles [2; 1-c] [1,4] oxazine-2-formaldehyde, yield 70%.
Claims (9)
1. morpholone mai verivate, it has the structure of being represented by formula I
2. the preparation method of a morpholone mai verivate of representing by formula I, this method comprises: makes 3-morpholone mai and Haloacetamide in solvent, in the presence of alkali, react according to following route, thereby generates the morpholone mai verivate of representing by formula I,
Wherein X is a chlorine or bromine.
3. method according to claim 2 is characterized in that, the molar ratio of 3-morpholone mai, said Haloacetamide and said alkali is 1: (1～2): (1～3), the reaction times is 0.5～48 hour.
4. method according to claim 3 is characterized in that, the molar ratio of 3-morpholone mai, said Haloacetamide and said alkali is 1: (1～1.5): (1～2), the reaction times is 12～24 hours.
5. method according to claim 2 is characterized in that, temperature of reaction be-80 ℃ to reflux temperature.
6. method according to claim 2; It is characterized in that; Said alkali is sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, calcium hydroxide, sodium methylate, sodium ethylate, sodium isopropylate, potassium isopropoxide, sodium tert-butoxide, potassium tert.-butoxide, sodium tert-amyl alcohol, tertiary amyl alcohol potassium, sodium hydrogencarbonate, saleratus, yellow soda ash, salt of wormwood, cesium carbonate, Quilonum Retard, sodium hydrogen, triethylamine, diisopropyl ethyl amine, tri-n-butylamine, pyridine or 2, the 6-lutidine.
7. method according to claim 6 is characterized in that, said alkali is sodium hydroxide, Pottasium Hydroxide or sodium methylate.
8. method according to claim 2; It is characterized in that; Said solvent is water, acetonitrile, methyl alcohol, ethanol, Virahol, sec-butyl alcohol, the trimethyl carbinol, 3-amylalcohol, 2-amylalcohol, tertiary amyl alcohol, 2-methyl-butanols, 3-methyl-3-amylalcohol, terepthaloyl moietie, ethylene glycol monomethyl ether, glycol dimethyl ether, glycerine, N; Dinethylformamide, N; N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, DMSO 99.8MIN., ETHYLE ACETATE, normal hexane, normal heptane, ether, sherwood oil, chloroform, methylene dichloride, THF, 2-methyltetrahydrofuran, 1,4-dioxane, benzene,toluene,xylene, sym-trimethylbenzene, chlorobenzene, dichlorobenzene or t-butyl methyl ether.
9. method according to claim 8 is characterized in that, said solvent is water, ethanol, THF, 1,4-dioxane or toluene.
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