CN101704796A - Preparation method of 3-morpholone - Google Patents
Preparation method of 3-morpholone Download PDFInfo
- Publication number
- CN101704796A CN101704796A CN200910131764A CN200910131764A CN101704796A CN 101704796 A CN101704796 A CN 101704796A CN 200910131764 A CN200910131764 A CN 200910131764A CN 200910131764 A CN200910131764 A CN 200910131764A CN 101704796 A CN101704796 A CN 101704796A
- Authority
- CN
- China
- Prior art keywords
- reaction
- preparation
- morpholone mai
- solvent
- morpholone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- VSEAAEQOQBMPQF-UHFFFAOYSA-N morpholin-3-one Chemical compound O=C1COCCN1 VSEAAEQOQBMPQF-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims description 21
- -1 2-acetyl chloride aminoethanol Chemical compound 0.000 claims abstract description 16
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 238000000926 separation method Methods 0.000 claims description 14
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 13
- 125000003368 amide group Chemical group 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 238000000746 purification Methods 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 11
- 239000012044 organic layer Substances 0.000 claims description 10
- 239000003513 alkali Substances 0.000 claims description 9
- 239000011230 binding agent Substances 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 238000011084 recovery Methods 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- JNLWIYBCSJXLIF-UHFFFAOYSA-N C([ClH]CCCCCCCCCCCCCC)C(C)O Chemical compound C([ClH]CCCCCCCCCCCCCC)C(C)O JNLWIYBCSJXLIF-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000000034 method Methods 0.000 abstract description 6
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 abstract 2
- 239000012346 acetyl chloride Substances 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- BQFCCCIRTOLPEF-UHFFFAOYSA-N chembl1976978 Chemical compound CC1=CC=CC=C1N=NC1=C(O)C=CC2=CC=CC=C12 BQFCCCIRTOLPEF-UHFFFAOYSA-N 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-trimethylbenzene Chemical compound CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 3
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 3
- QPRQEDXDYOZYLA-UHFFFAOYSA-N 2-methylbutan-1-ol Chemical class CCC(C)CO QPRQEDXDYOZYLA-UHFFFAOYSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229940117389 dichlorobenzene Drugs 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 2
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229920006149 polyester-amide block copolymer Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- WQKGAJDYBZOFSR-UHFFFAOYSA-N potassium;propan-2-olate Chemical compound [K+].CC(C)[O-] WQKGAJDYBZOFSR-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a synthetic process of 3-morpholone. The traditional method for synthesizing the compound at home and abroad needs to use sodium metal or sodium-hydrogen and has high equipment investment and complex operation. In the synthetic process, 2-acetyl chloride aminoethanol generated by ethanolamine and chloroacetic chloride generates morpholone through ring closing reaction under the action of alkaline. The synthetic process has simpleness, low equipment requirement, simple operation, high product yield and good quality and is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation method of 3-morpholone mai.
Background technology
Morpholone mai is a kind of important compound.People are very interested in the compound of this class formation, and especially the research of 3-morpholone mai derivative more and more is subjected to people's attention, for example US6265402, US3308121, US6265402B1, CN1736992.The 3-morpholone mai is to produce multiple medicine and novel high polymer material (for example: important intermediate polyesteramide), it is widely used in organic synthesis, macromolecular material and pharmaceutical industry field.Produced (the J.Wuhan Univ. (Nat.Sci.Ed.) 2004 that this product mainly utilizes sodium Metal 99.5, thanomin and ethyl chloroacetate to produce in the past, 50, (2), 173-176, Journal ofPolymer Science, Part A Polymer Chemistry 2002,40, (24), 4550-4555, and US5349045); Or utilize sodium hydrogen, thanomin and ethyl chloroacetate to produce (W02006063113); Or utilize sodium Metal 99.5, thanomin and Mono Chloro Acetic Acid to produce (US4372974).Make a general survey of the 3-morpholone mai synthetic method of having delivered, no matter being to use sodium Metal 99.5 still is that the synthetic method of sodium hydrogen all exists complicated operation, the equipment requirements height, and therefore big the and low defective of yield of potential safety hazard is difficult to be applied to amplify production.
By retrieval, in the synthetic and preparation method of known 3-morpholone mai, current also do not have an industrial method of avoiding using sodium Metal 99.5 or sodium hydrogen and producing the 3-morpholone mai.
Summary of the invention
The preparation method who the purpose of this invention is to provide a kind of 3-morpholone mai, this method has overcome in the conventional production 3-morpholone mai method, owing to need to use sodium Metal 99.5 or sodium hydrogen,, and be easy to suitability for industrialized production to equipment requirements height, potential safety hazard is big and yield is low defective.
For achieving the above object, the preparation method according to production 3-morpholone mai of the present invention comprises steps A: ring-closure reaction is taken place in solvent orange 2 A for 2-chloracetyl amido ethanol and alkali prepare the 3-morpholone mai, reaction formula is as follows:
Especially, above-mentioned steps A reaction can be carried out under the reflux temperature of-80 ℃～solvent orange 2 A, and the mol ratio of 2-chloracetyl ethanol and alkali is 1: (1～2), the reaction times is 0.5～48 hour.
Preferably, after the steps A reaction finishes, also comprise the separation purification step of 3-morpholone mai.
Preferably, the reacted separation purification step of described steps A comprises: (1) regulates PH=7; (2) Separation and Recovery solvent orange 2 A; (3) extraction and collected organic layer; And (4) re-crystallization step.
According to one embodiment of present invention, under-80 ℃～solvent orange 2 A reflux temperature, 2-chloracetyl amido ethanol and alkali are 1 with its mole number: the ratio of (1～2) joins in the solvent orange 2 A, under-80 ℃～solvent orange 2 A reflux temperature, reacts 0.5～48 hour; After described separation purification step is included in the reaction end, adds 37% concentrated hydrochloric acid and transfer PH=7, heating up steams solvent orange 2 A, remaining mixture is chilled to room temperature, the water that adds 5～10 times of remaining mixture volumes is used the methylene dichloride or the ethyl acetate extraction of 2～10 times of water yields, triplicate again, use anhydrous sodium sulfate drying, filter, be evaporated to dried crude product, add the solvent C dissolving, room temperature or be cooled to-80 ℃～25 ℃ recrystallizations 1～48 hour is filtered the crystal oven dry that obtains and is promptly made the 3-morpholone mai.
The described solvent orange 2 A of steps A can be selected from water, acetonitrile, methyl alcohol, ethanol, Virahol, sec-butyl alcohol, the trimethyl carbinol, the 3-amylalcohol, the 2-amylalcohol, tertiary amyl alcohol, 2-methyl-butanols, 3-methyl-3-amylalcohol, ethylene glycol, ethylene glycol monomethyl ether, glycol dimethyl ether, glycerine, N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), ethyl acetate, normal hexane, normal heptane, ether, sherwood oil, chloroform, methylene dichloride, tetrahydrofuran (THF), the 2-methyltetrahydrofuran, 1, the 4-dioxane, benzene, toluene, dimethylbenzene, sym-trimethylbenzene, chlorobenzene, dichlorobenzene, t-butyl methyl ether.
Alkali described in the steps A can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, 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 bicarbonate, saleratus, yellow soda ash, salt of wormwood, cesium carbonate, Quilonum Retard, sodium hydrogen, triethylamine, diisopropyl level ethylamine, tri-n-butylamine, pyridine, 2,6-lutidine.
Employed described solvent C is selected from water in the steps A reaction back separation purification step, acetonitrile, methyl alcohol, ethanol, Virahol, sec-butyl alcohol, the trimethyl carbinol, the 3-amylalcohol, the 2-amylalcohol, tertiary amyl alcohol, 2-methyl-butanols, 3-methyl-3-amylalcohol, ethylene glycol, ethylene glycol monomethyl ether, glycol dimethyl ether, glycerine, N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), ethyl acetate, normal hexane, normal heptane, ether, sherwood oil, chloroform, methylene dichloride, tetrahydrofuran (THF), the 2-methyltetrahydrofuran, 1, the 4-dioxane, benzene, toluene, dimethylbenzene, sym-trimethylbenzene, chlorobenzene, dichlorobenzene, t-butyl methyl ether.
Wherein, the solvent orange 2 A described in the steps A is preferably water, ethanol, tetrahydrofuran (THF), 1,4-dioxane, toluene; Described alkali is preferably sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate; It is 1 that the mole ratio of 2-chloracetyl amido ethanol and alkali is preferably: (1～1.2); Reaction times under the solvent orange 2 A reflux temperature is preferably 12～24 hours.
Employed described solvent C is preferably tetrahydrofuran (THF), 1,4-dioxane, toluene, ether, ethyl acetate in the reacted separation purification step of steps A.
2-chloracetyl amido ethanol can be commercial also synthetic voluntarily.Preferably, the 2-chloracetyl amido ethanol in the preparation in accordance with the present invention can prepare by step B: in solvent B, thanomin reacts with chloroacetyl chloride in the presence of acid binding agent, and reaction formula is as follows:
Especially, above-mentioned steps B reaction can be carried out under the reflux temperature of-80 ℃～solvent B, and the reaction times is 0.5～48 hour, and the mol ratio of thanomin and acid binding agent is 1: 1～1: 2, and the mol ratio of thanomin and chloroacetyl chloride is 1: 1～1: 2.
Preferably, after above-mentioned steps B reaction finishes, comprise that 2-chloracetyl amido alcoholic acid separates purification step.
Preferably, the reacted separation purification step of described step B comprises: (1) Separation and Recovery solvent B; (2) extraction and collected organic layer; (3) concentrating under reduced pressure.
According to one embodiment of present invention, described step B reaction is: thanomin, acid binding agent are 1 with its mole number: the ratio of (1～2) and solvent B put in the reactor, measure the adding chloroacetyl chloride to be 1～2 times with the thanomin mol ratio, under-80 ℃～solvent B reflux temperature, reacted 0.5～48 hour; The reacted separation purification step of described step B comprises: heating up steams solvent B, remaining mixture is chilled to room temperature, the water that adds 5～10 times of remaining mixture volumes, use the methylene dichloride or the ethyl acetate extraction of 2～10 times of water yields again, triplicate is used anhydrous sodium sulfate drying, filters, concentrating under reduced pressure promptly gets 2-chloracetyl amido ethanol
The described solvent B of step B can be selected from water, acetonitrile, methyl alcohol, ethanol, Virahol, sec-butyl alcohol, the trimethyl carbinol, the 3-amylalcohol, the 2-amylalcohol, tertiary amyl alcohol, 2-methyl-butanols, 3-methyl-3-amylalcohol, ethylene glycol, ethylene glycol monomethyl ether, glycol dimethyl ether, glycerine, N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, dimethyl sulfoxide (DMSO), ethyl acetate, normal hexane, normal heptane, ether, sherwood oil, chloroform, methylene dichloride, tetrahydrofuran (THF), the 2-methyltetrahydrofuran, 1, the 4-dioxane, benzene, toluene, dimethylbenzene, sym-trimethylbenzene, chlorobenzene, dichlorobenzene, t-butyl methyl ether.
The described acid binding agent of step B can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium bicarbonate, saleratus, yellow soda ash, salt of wormwood, cesium carbonate, Quilonum Retard, triethylamine, diisopropyl level ethylamine, tri-n-butylamine, pyridine, 2,6-lutidine.
The described acid binding agent of step B is preferably and is selected from sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, triethylamine, pyridine; The mole ratio of thanomin and acid binding agent is preferably 1: (1.1～1.5); Described solvent B is preferably and is selected from water, acetonitrile, methylene dichloride, tetrahydrofuran (THF), 1,4-dioxane, toluene; The mole ratio of thanomin and chloroacetyl chloride is preferably 1: (1.1～1.5); Reaction times under the solvent B reflux temperature is preferably 2～6 hours.
The 3-morpholone mai of the present invention's preparation has in organic synthesis, macromolecular material and pharmaceutical industry field widely to be used.
Embodiment
Describe the present invention below in conjunction with embodiment, but content of the present invention is not limited to this fully.
The preparation of embodiment 1:3-morpholone mai
Step 1:2-chloracetyl amido ethanol
61 gram thanomins and 151.7 gram triethylamines are dissolved in 800 milliliters of methylene dichloride, and 0 ℃ under agitation drips 169.4 gram chloroacetyl chlorides, after dropwising, stirring at room 6 hours adds 800 ml waters in the reaction solution, tell dichloromethane layer, water layer is with 300 milliliters of dichloromethane extractions, and triplicate merges organic layer, anhydrous sodium sulfate drying, concentrate, obtain yellow oil 122.4 grams, yield 89%, without being further purified, can be directly used in next step reaction.
Step 2:3-morpholone mai
122.4 gram 2-chloracetyl amido ethanol is dissolved in 100 ml waters, 180 grams, 20% aqueous sodium hydroxide solution splashes in room temperature, and 30 ℃ were reacted 24 hours, and the frozen water cooling adds 37% concentrated hydrochloric acid down and transfers PH=7, add 300 milliliters of ethyl acetate extractions, triplicate, the organic layer anhydrous sodium sulfate drying filters, be evaporated to dried, add 500 milliliters of ether recrystallizations, recrystallization temperature is-30 ℃, and crystallization time is 48 hours.The crystal oven dry that filtration obtains promptly makes 3-morpholone mai 73.8 grams, yield 82%.
Structural formula is as follows:
Molecular formula: C
4H
7NO
2
Molecular weight: 101.1
Proterties: colourless acicular crystal
Fusing point: 104-105 ℃
Nucleus magnetic resonance and mass-spectrometric data are as follows:
1H?NMR(500MHz，CDCl
3)：δ8.13(s，1H)，4.15(s，2H)，3.83(t，J＝5.0Hz，2H)，3.41(m，2H)；
13C?NMR(125MHz，CDCl
3)：δ169.3，67.3，62.9，40.8；
MS(EI)：(m/z)＝101(M
+).
The preparation of embodiment 2:3-morpholone mai
Step 1:2-chloracetyl amido ethanol
61 gram thanomins and 50 gram dissolution of sodium hydroxide are in 800 ml waters, and 0 ℃ under agitation drips methylene dichloride (300 milliliters) solution that contains 135.54 gram chloroacetyl chlorides, after dropwising, stirring at room 3 hours is told dichloromethane layer, and water layer is with 300 milliliters of dichloromethane extractions, triplicate, merge organic layer, anhydrous sodium sulfate drying concentrates, obtain yellow oil 107.3 grams, yield 78% without being further purified, can be directly used in next step reaction.
Step 2:3-morpholone mai
107.3 gram 2-chloracetyl amido ethanol is dissolved in 100 milliliters of ethanol, 600 milliliters of ethanolic solns that contain 63.7 gram sodium ethylates splash in room temperature, after dropwising, 30 ℃ were reacted 12 hours, reaction solution is chilled to room temperature, splash into 200 milliliters in water, the frozen water cooling adds 37% concentrated hydrochloric acid down and transfers PH=7, and ethanol is reclaimed in underpressure distillation, add 300 milliliters of ethyl acetate extractions in the residuum, triplicate, the organic layer anhydrous sodium sulfate drying filters, be evaporated to dried, add 600 milliliters of toluene recrystallizations, recrystallization temperature is-20 ℃, and crystallization time is 36 hours.The crystal oven dry that filtration obtains promptly makes 3-morpholone mai 59.1 grams, yield 75%.
The preparation of embodiment 3:3-morpholone mai
Step 1:2-chloracetyl amido ethanol
61 gram thanomins and 166 gram salt of wormwood are suspended in 800 milliliters of tetrahydrofuran (THF)s, 0 ℃ under agitation drips 169.4 gram chloroacetyl chlorides, after dropwising, stirring at room 6 hours, tetrahydrofuran (THF) is reclaimed in underpressure distillation, add 200 ml waters and 300 milliliters of methylene dichloride in the reaction solution, tell dichloromethane layer, water layer is with 300 milliliters of dichloromethane extractions, triplicate, merge organic layer, anhydrous sodium sulfate drying concentrates, obtain yellow oil 110 grams, yield 80% without being further purified, can be directly used in next step reaction.
Step 2:3-morpholone mai
110 gram 2-chloracetyl amido ethanol are dissolved in 100 milliliters of ethanol, 800 milliliters of ethanolic solns that are dissolved with 44.9 gram potassium hydroxide splash in room temperature, after dropwising, 30 ℃ were reacted 24 hours, reaction solution is chilled to room temperature, splash into 200 milliliters in water, the frozen water cooling adds 37% concentrated hydrochloric acid down and transfers PH=7, and ethanol is reclaimed in underpressure distillation, adds 300 milliliters of ethyl acetate extractions, triplicate, the organic layer anhydrous sodium sulfate drying filters, and is evaporated to 400 milliliters of ethyl acetate decrease temperature crystallines of residue, Tc is-20 ℃, and crystallization time is 24 hours.The crystal oven dry that filtration obtains promptly makes 3-morpholone mai 58.2 grams, yield 72%.
Claims (10)
1. the preparation method of a 3-morpholone mai comprises steps A:, ring-closure reaction in solvent, is taken place and prepares the 3-morpholone mai in 2-chloracetyl amido ethanol and alkali.
2. the preparation method of 3-morpholone mai according to claim 1 is characterized in that reaction conditions is: temperature of reaction by-80 ℃～the reflux temperature of use solvent, reaction times 0.5-48 hour, be preferably and under the reflux temperature of solvent, reacted 12～24 hours; The mol ratio of 2-chloracetyl ethanol and alkali is between 1: 1～1: 2, be preferably 1: 1～and between 1: 1.2.
3. the preparation method of 3-morpholone mai according to claim 1 is characterized in that described alkali is selected from sodium hydroxide, potassium hydroxide, sodium methylate and sodium ethylate, and described solvent is selected from water, ethanol, tetrahydrofuran (THF), 1,4-dioxane, toluene.
4. according to the preparation method of each described 3-morpholone mai among the claim 1-3, after the reaction that it is characterized in that steps A finishes, also comprise the separation purification step of 3-morpholone mai.
5. the preparation method of 3-morpholone mai according to claim 4 is characterized in that described separation purification step comprises: (1) regulates PH=7; (2) Separation and Recovery is reacted employed solvent; (3) extraction and collected organic layer; And (4) re-crystallization step.
6. the preparation method of 3-morpholone mai according to claim 1, it is characterized in that, described 2-chloracetyl amido ethanol passes through step B prepared in reaction: under the condition that acid binding agent exists, thanomin and chloroacetyl chloride be prepared in reaction 2-chloracetyl amido ethanol in solvent.
7. the preparation method of 3-morpholone mai according to claim 6, it is characterized in that described step B reaction conditions is: be reflected at temperature of reaction by-80 ℃～carry out under the reflux temperature of use solvent, reaction times is 0.5～48 hour, is preferably to react under the reflux temperature of use solvent 2～6 hours; The mol ratio of thanomin and acid binding agent is 1: 1～1: 2, is preferably 1: 1.1～1: 1.5, and the mol ratio of thanomin and chloroacetyl chloride is 1: 1～1: 2, is preferably 1: 1.1～1: 1.5.
8. the preparation method of 3-morpholone mai according to claim 6, it is characterized in that: described acid binding agent is selected from sodium hydroxide, potassium hydroxide, salt of wormwood, triethylamine, pyridine, described solvent is selected from water, acetonitrile, methylene dichloride, tetrahydrofuran (THF), 1,4-dioxane, toluene.
9. according to the preparation method of each described 3-morpholone mai among the claim 6-8, it is characterized in that comprising that also 2-chloracetyl amido alcoholic acid separates purification step after described step B reaction finishes.
10. the preparation method of 3-morpholone mai according to claim 9,2-chloracetyl amido alcoholic acid separation purification step comprises under it is characterized in that: the employed solvent of reaction among (1) Separation and Recovery step B; (2) extraction and collected organic layer; (3) concentrating under reduced pressure.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101317643A CN101704796B (en) | 2009-04-01 | 2009-04-01 | Preparation method of 3-morpholone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101317643A CN101704796B (en) | 2009-04-01 | 2009-04-01 | Preparation method of 3-morpholone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101704796A true CN101704796A (en) | 2010-05-12 |
| CN101704796B CN101704796B (en) | 2011-12-21 |
Family
ID=42375060
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009101317643A Expired - Fee Related CN101704796B (en) | 2009-04-01 | 2009-04-01 | Preparation method of 3-morpholone |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101704796B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804316A (en) * | 2012-11-13 | 2014-05-21 | 天津药物研究院 | Preparation method of (2RS, 3RS)-6-[a-(2-ethoxyl phenoxyl) benzyl] morpholine-3-one (I) |
| CN103880768A (en) * | 2014-02-26 | 2014-06-25 | 南通大学 | Chemical synthesis method of 3-cyclobutylmorpholine |
| CN104356086A (en) * | 2014-11-28 | 2015-02-18 | 湖南科技大学 | Preparation method of 3-morpholone suitable for industrial production |
| CN115947697A (en) * | 2022-12-28 | 2023-04-11 | 苏州汉德创宏生化科技有限公司 | Synthesis method of 3-oxomorpholine-4-carboxylic acid tert-butyl ester |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102746288B (en) * | 2012-07-24 | 2015-04-08 | 常州制药厂有限公司 | Preparation methods of anticoagulant and key intermediate of anticoagulant |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5349045A (en) * | 1993-01-26 | 1994-09-20 | United States Surgical Corporation | Polymer derived from cyclic amide and medical devices manufactured therefrom |
-
2009
- 2009-04-01 CN CN2009101317643A patent/CN101704796B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804316A (en) * | 2012-11-13 | 2014-05-21 | 天津药物研究院 | Preparation method of (2RS, 3RS)-6-[a-(2-ethoxyl phenoxyl) benzyl] morpholine-3-one (I) |
| CN103880768A (en) * | 2014-02-26 | 2014-06-25 | 南通大学 | Chemical synthesis method of 3-cyclobutylmorpholine |
| CN103880768B (en) * | 2014-02-26 | 2016-04-13 | 南通大学 | A kind of chemical synthesis process of 3-cyclobutyl morpholine |
| CN104356086A (en) * | 2014-11-28 | 2015-02-18 | 湖南科技大学 | Preparation method of 3-morpholone suitable for industrial production |
| CN115947697A (en) * | 2022-12-28 | 2023-04-11 | 苏州汉德创宏生化科技有限公司 | Synthesis method of 3-oxomorpholine-4-carboxylic acid tert-butyl ester |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101704796B (en) | 2011-12-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102627573B (en) | Synthesis method for 5-aminolevulinic acid hydrochloride | |
| KR101466245B1 (en) | Method for preparing methanesulfonic acid salt and novel compound used therein | |
| CN101704796B (en) | Preparation method of 3-morpholone | |
| CN112110828A (en) | Synthesis method of pipadiric acid and intermediate thereof | |
| US11401235B2 (en) | Synthesis of terphenyl compounds | |
| CN102351778A (en) | Preparation method of arbidol hydrochloride | |
| CA2670282A1 (en) | A new method for preparing 4,4'-(1-methyl-1,2-ethandiyl)-bis-(2,6-piperazinedione) | |
| CN102863359A (en) | Synthesis method of anti-flu medicine | |
| CN103373963B (en) | Intermediate of pazopanib hydrochloride and preparation method thereof | |
| CN103288693B (en) | Method for preparing 1-mercaptopyrene and intermediate compound thereof | |
| CN103739541B (en) | The preparation method of 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-piperidino) phenyl]-2 (1H)-pyridones | |
| CN114539285A (en) | A kind of preparation method of mabaloxavir | |
| CN102731368A (en) | Preparation method of 5,5-difluoro-3-substituted piperidine derivative | |
| WO2015012271A1 (en) | Method for producing heterocyclic compound | |
| KR20130054250A (en) | A process for the preparation of highly pure ambrisentan | |
| CN103012261A (en) | Method for preparing montelukast sodium and intermediate of montelukast sodium | |
| CN116332935B (en) | Synthesis method of folic acid | |
| CN116813505A (en) | A method for preparing O-methyl-N-benzyloxycarbonyl-L-homoserine | |
| CN113698392B (en) | A preparation method of Prunster intermediate | |
| CN111574463A (en) | Riagliptin intermediate compound IV | |
| CN108689957A (en) | A kind of preparation method and application of 2R/2S- trifluoromethyls morpholine and its hydrochloride | |
| JPS62187467A (en) | Novel production of 4-acetylisoquinoline compound | |
| CN120309497A (en) | A preparation method of nedocromil intermediate | |
| CN102020616B (en) | Method for preparing 2-(3-oxo-morpholine) acetonitrile | |
| US20050165054A1 (en) | Process for the preparation of quinoline derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20111221 Termination date: 20180401 |