CN103382200A - Preparation method of S-glycidylphthalimide - Google Patents
Preparation method of S-glycidylphthalimide Download PDFInfo
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- CN103382200A CN103382200A CN2012101309954A CN201210130995A CN103382200A CN 103382200 A CN103382200 A CN 103382200A CN 2012101309954 A CN2012101309954 A CN 2012101309954A CN 201210130995 A CN201210130995 A CN 201210130995A CN 103382200 A CN103382200 A CN 103382200A
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- phthalic imidine
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- racemic glycidol
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims abstract description 123
- 238000006243 chemical reaction Methods 0.000 claims abstract description 92
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 claims abstract description 42
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 28
- 238000003756 stirring Methods 0.000 claims description 54
- 235000007715 potassium iodide Nutrition 0.000 claims description 40
- 229960004839 potassium iodide Drugs 0.000 claims description 40
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims description 39
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 claims description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 33
- 239000002904 solvent Substances 0.000 claims description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 8
- -1 polyoxyethylene Polymers 0.000 claims description 8
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 6
- OFJRNBWSFXEHSA-UHFFFAOYSA-N 2-(3-amino-1,2-benzoxazol-5-yl)-n-[4-[2-[(dimethylamino)methyl]imidazol-1-yl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide Chemical compound CN(C)CC1=NC=CN1C(C=C1F)=CC=C1NC(=O)C1=CC(C(F)(F)F)=NN1C1=CC=C(ON=C2N)C2=C1 OFJRNBWSFXEHSA-UHFFFAOYSA-N 0.000 claims description 5
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 claims description 5
- 229960003907 linezolid Drugs 0.000 claims description 5
- 229950010535 razaxaban Drugs 0.000 claims description 5
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 5
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 4
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 4
- CEYYIKYYFSTQRU-UHFFFAOYSA-M trimethyl(tetradecyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)C CEYYIKYYFSTQRU-UHFFFAOYSA-M 0.000 claims description 4
- AJSHDAOMUKXVDC-UHFFFAOYSA-N butan-1-amine;sulfuric acid Chemical compound CCCC[NH3+].OS([O-])(=O)=O AJSHDAOMUKXVDC-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 10
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- BRLQWZUYTZBJKN-GSVOUGTGSA-N (+)-Epichlorohydrin Chemical compound ClC[C@@H]1CO1 BRLQWZUYTZBJKN-GSVOUGTGSA-N 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 239000002994 raw material Substances 0.000 description 30
- 239000007787 solid Substances 0.000 description 29
- 238000005406 washing Methods 0.000 description 26
- 238000000967 suction filtration Methods 0.000 description 25
- 238000001035 drying Methods 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 5
- 239000012265 solid product Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- LRWZZZWJMFNZIK-ZJRLKYRESA-N (2s)-2-chloro-3-methyloxirane Chemical compound CC1O[C@H]1Cl LRWZZZWJMFNZIK-ZJRLKYRESA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- XISFOXBYRQWDNK-UHFFFAOYSA-N 2-(2-methylphenyl)propan-2-amine;hydrochloride Chemical compound [Cl-].CC1=CC=CC=C1C(C)(C)[NH3+] XISFOXBYRQWDNK-UHFFFAOYSA-N 0.000 description 1
- FQGIBHQUVCGEAC-UHFFFAOYSA-N 3-Fluoro-4-morpholinoaniline Chemical compound FC1=CC(N)=CC=C1N1CCOCC1 FQGIBHQUVCGEAC-UHFFFAOYSA-N 0.000 description 1
- MHCRLDZZHOVFEE-UHFFFAOYSA-N 4-(4-aminophenyl)morpholin-3-one Chemical compound C1=CC(N)=CC=C1N1C(=O)COCC1 MHCRLDZZHOVFEE-UHFFFAOYSA-N 0.000 description 1
- PUZWEHOSFBXSQS-UHFFFAOYSA-N 4-oxo-2H-1,3-oxazol-2-ide-5-sulfonic acid Chemical compound S(=O)(=O)(O)C1C(N=[C-]O1)=O PUZWEHOSFBXSQS-UHFFFAOYSA-N 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003324 growth hormone secretagogue Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- GQJOLWWRVLESSJ-UHFFFAOYSA-N morpholine;urea Chemical class NC(N)=O.C1COCCN1 GQJOLWWRVLESSJ-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229940127066 new oral anticoagluant drug Drugs 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- COWNFYYYZFRNOY-UHFFFAOYSA-N oxazolidinedione Chemical compound O=C1COC(=O)N1 COWNFYYYZFRNOY-UHFFFAOYSA-N 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000009666 routine test Methods 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
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- Indole Compounds (AREA)
Abstract
The invention relates to a preparation method of S-glycidylphthalimide. The preparation method is characterized in that in a reaction of potassium phthalimide or phthalimide and (S) epichlorohydrin, a phase transfer catalyst and potassium iodide are used so that S-glycidylphthalimide synthesis is realized. Compared with the prior art, the preparation method greatly improves an S-glycidylphthalimide yield, has simple and safe processes, produces high-purity products, has a low cost and is suitable for industrial production of S-glycidylphthalimide.
Description
Technical field
The present invention relates to the field of chemical synthesis, be specifically related to a kind of preparation method of S-Racemic glycidol phthalic imidine.
Background technology
S-Racemic glycidol phthalic imidine is the important intermediate of the oxazolidinones such as preparation new antibiotic Linezolid, new oral anticoagulant razaxaban, simultaneously be also the antimycotic sulfo-oxazolidone of preparation, oxazolidinedione, as the amide compound of growth hormone secretagogues, be used for the treatment of the important intermediate of the heterogeneous ring compounds such as morpholine urea derivatives of inflammation.
The preparation method of S-Racemic glycidol phthalic imidine normally adopts the people such as A.Gutcait at Tetrahedron Asym.1996, and the method described in 7,1641 is synthetic.The method be take phthalic imidine and (S) epoxy chloropropane as raw material, at diethylazodicarboxylate (DEAD) and triphenyl phosphine (PH
3P) under existence, make solvent with tetrahydrofuran (THF), made in 18 hours at the temperature range internal reactions of 20 ℃～25 ℃, but this reaction has generated the by product that more difficulty is removed, and reaction yield is lower, and yield is 30% left and right only, purity only 60%, not only aftertreatment is loaded down with trivial details, and production cost is high.
WO 2007074686 disclose a kind of take phthalic imidine and (S) epoxy chloropropane as raw material, in the situation that potassium tert.-butoxide and three normal-butyl ammoniums exist in Virahol reaction to prepare the method for S-Racemic glycidol phthalic imidine in 24 hours.But this reaction yield in actual tests is only 30% left and right, and the highest yield is only 36%, and purity causes with this method suitability for industrialized production S-Racemic glycidol phthalic imidine cost higher in 80% left and right.
EP1403267 discloses take potassium phthalimide as raw material, stirring reaction solvent evaporated after 46 hours in the isopropanol solvent of trimethyl benzyl ammonia chloride and epoxy chloropropane, washing adds ethyl acetate and normal hexane recrystallization to get the preparation method of S-Racemic glycidol phthalic imidine.But in this reaction actual tests, yield is lower, is only 30% left and right, and purity is about 70% left and right, causes S-Racemic glycidol phthalic imidine production cost high.
Bogda etc. are at Synlett, Vol.1996. 873-974, disclose in Remarkable fast microwave-assisted N-Alkylation of Phthalimide in dry media a kind of take phthalic imidine and (S) epoxy chloropropane as raw material, under tetrabutylammonium iodide and salt of wormwood existence, reaction prepares the method for S-Racemic glycidol phthalic imidine in microwave.But because microwave reaction is the closed system reaction, with certain danger, the laboratory that is only suitable in a small amount is synthetic, and after amplifying production, its danger coefficient increases greatly, is unsuitable for industrial production.
Therefore, the widespread use clinically of the oxazolidinones such as Linezolid and razaxaban, need to seek a kind of high yield, easy and simple to handle, technical process is simple, safety, be fit to suitability for industrialized production the preparation method of S-Racemic glycidol phthalic imidine, and the S-Racemic glycidol phthalic imidine purity for preparing by the method is high, and it is very necessary that by product becomes less.
Summary of the invention
One of purpose of the present invention is that a kind of yield is high, by product is few, cost is low, easy and simple to handle, technical process is simple in order to provide, and is fit to the preparation method of the S-Racemic glycidol phthalic imidine of suitability for industrialized production.
To achieve these goals, the invention provides following technical proposals:
One aspect of the present invention provides a kind of preparation method of S-Racemic glycidol phthalic imidine, it specifically is included in the reaction of the adjacent potassium phthalimide of raw material or Phthalimide and (S)-epoxy chloropropane, has added phase-transfer catalyst and potassiumiodide.
The mol ratio of potassiumiodide described in such scheme and potassium phthalimide or phthalic imidine is preferably 1:1000～1:1, is preferably 1:200～1:20, more preferably 1:100.
The mol ratio of phase-transfer catalyst described in such scheme and potassium phthalimide or phthalic imidine is preferably and is 1:100～1:1, is preferably 1:20～1:5, more preferably 1:10.
Described in such scheme, the mol ratio of (S) epoxy chloropropane and potassium phthalimide or phthalic imidine is preferably 10:1～1:1, is preferably 5:1～1:1, more preferably 2:1.
Phase-transfer catalyst described in such scheme is preferably one or more in benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, three normal-butyl ammoniums, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, chain polyoxyethylene glycol, cyclic crown ether, most preferably is benzyltriethylammoinium chloride.
The present invention also further provides the preparation method who comprises following reactions steps, concrete steps are as follows: add potassium phthalimide, phase-transfer catalyst, potassiumiodide, solvent in reactor, or add phthalic imidine, potassium tert.-butoxide, phase-transfer catalyst, potassiumiodide, solvent in reactor, add (S) epoxy chloropropane in the temperature range of 25 ℃～40 ℃, and in the temperature range of 25 ℃～40 ℃ stirring reaction.
The preparation method of the S-Racemic glycidol phthalic imidine described in above-mentioned preparation method preferably adds (S) epoxy chloropropane in the temperature range of 28 ℃～32 ℃, and in the temperature range of 28 ℃～32 ℃ stirring reaction.
Described in above-mentioned preparation method, solvent is preferably one or more in methyl alcohol, ethanol and Virahol, most preferably is Virahol.
Solvent described in above-mentioned preparation method is preferably 20:1～3:1 with the volume mass of potassium phthalimide or phthalic imidine than (ml/g), is preferably 10:1～4:1, most preferably is 4.5:1.
The present invention also provides by above-mentioned preparation method and has made S-Racemic glycidol phthalic imidine, the application in the Oxazolidinone derivative such as synthetic Linezolid or razaxaban or other heterogeneous ring compounds.
The present patent application people is when adopting (S)-epoxy chloropropane and potassium phthalimide at 30 ℃, the reaction take Virahol as stirring solvent, find during with preparation S-Racemic glycidol phthalic imidine, reach 100 hours when the reaction times, thin-layer chromatography monitoring reaction is not carried out fully yet, suction filtration after filtration cakes torrefaction, finds that resulting S-Racemic glycidol phthalic imidine product yield is only 10%-20%.
The present application people attempts increasing the stir speed (S.S.) of above-mentioned reaction and improves temperature of reaction, to improving the yield of potassium phthalimide and epichlorohydrin reaction, Reaction time shorten, but when stirring velocity reaches Routine Test Lab mechanical stirring maximum speed of revolution, when temperature of reaction reaches 80 ℃, still extremely faint to the raising of reaction yield.
The present application people is in order to improve yield, improve speed of response, except adding potassium phthalimide, also add potassiumiodide as catalyzer in reactor, to improving the reactive behavior of epoxy chloropropane, but when in Virahol, 30 ℃ of reaction times reach 50 hours, and thin-layer chromatography monitoring reaction is not carried out fully yet, suction filtration, after filtration cakes torrefaction, find that resulting S-Racemic glycidol phthalic imidine product yield is only 10%-20%.
The present application people again according to the report of WO 2007074686 take phthalic imidine and (S) epoxy chloropropane as raw material, in the situation that existing when reaction got S-Racemic glycidol phthalic imidine in 24 hours in Virahol, potassium tert.-butoxide and three normal-butyl ammoniums find, the document yield can repeat out, take the highest yield of this method test of many times only as 36%, continue reaction after 48 hours, find that resulting S-Racemic glycidol phthalic imidine product yield is only 35% left and right.
In order to improve yield, the present application people attempts substituting three normal-butyl ammoniums with benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, alpha-cylodextrin or chain polyoxyethylene glycol and makes phase-transfer catalyst, take potassium phthalimide and (S) epoxy chloropropane as raw material, 30 ℃ were reacted 48 hours in Virahol, suction filtration, after filtration cakes torrefaction, the highest yield of resulting S-Racemic glycidol phthalic imidine product is still lower than 40%.
The present patent application people attempts changing reaction solvent to improve reaction yield, take potassium phthalimide and (S) epoxy chloropropane as raw material, in the situation that existing in ethanol, three normal-butyl ammoniums reacted 48 hours, the yield of resulting S-Racemic glycidol phthalic imidine product is only 26%, reaction is 48 hours in methyl alcohol, and the yield of resulting S-Racemic glycidol phthalic imidine product is 18%.
The present patent application people attempts being added to maximum with benzyltriethylammoinium chloride as the consumption of phase-transfer catalyst, and namely the mol ratio of phase-transfer catalyst and raw material is 1:1, but also also not obvious to the raising of reaction yield.
After the present patent application people studies through lot of experiments, find uncannily, take potassium phthalimide as raw material or take phthalic imidine and potassium tert.-butoxide as raw material, take methyl alcohol, ethanol or Virahol as solvent, when phase-transfer catalyst and potassiumiodide exist simultaneously, can make the yield of reaction obtain surprising lifting.
the present patent application people's research knows that the mol ratio when phase-transfer catalyst and raw material is 1:100～1:1, the mol ratio of potassiumiodide and raw material is 1:1000～1:1, when (S) mol ratio of epoxy chloropropane and raw material is 10:1～1:1, temperature of reaction is in the temperature range of 25 ℃～40 ℃, the volume of solvent (ml): when the quality of raw material (g) is 20:1～3:1, the yield of reaction can reach more than 50%, purity is at 80%-95%, when with Virahol as solvent, can obtain than with methyl alcohol, better yield when ethanol is solvent, under above-mentioned reaction conditions, take Virahol as solvent, yield can reach more than 70%, purity is at 80%-95%.
when add potassium phthalimide in reactor, phase-transfer catalyst, potassiumiodide, or add phthalic imidine, potassium tert.-butoxide, phase-transfer catalyst, potassiumiodide, with methyl alcohol, ethanol is solvent, and the mol ratio of phase-transfer catalyst and raw material is 1:20～1:5, the mol ratio of potassiumiodide and raw material is 1:200～1:20, when (S) mol ratio of epoxy chloropropane and raw material is 5:1～1:1, temperature of reaction is in the temperature range of 25 ℃～40 ℃, the volume of solvent (ml): when the quality of raw material (g) is 10:1～4:1, the yield of reaction can reach more than 60%, purity is at 80%-95%, if with Virahol as solvent, under above-mentioned reaction conditions, yield can reach more than 80%, purity is at 80%-95%.
most preferred, when add potassium phthalimide in reactor, phase-transfer catalyst, potassiumiodide, or add phthalic imidine, potassium tert.-butoxide, phase-transfer catalyst, potassiumiodide, with methyl alcohol, ethanol is solvent, and the mol ratio of phase-transfer catalyst and raw material is 1:10, the mol ratio of potassiumiodide and raw material is 1:100, when (S) mol ratio of epoxy chloropropane and raw material is 2:1, temperature of reaction is in the temperature range of 28 ℃～32 ℃, the volume of solvent (ml): when the quality of raw material (g) is 4.5:1, the yield of reaction can reach more than 70%, purity is at 80%-95%, if with Virahol as solvent, under above-mentioned reaction conditions, yield can reach more than 90%, purity is at 80%-95%.
the present application people is also known under study for action, when add potassium phthalimide in reactor, benzyltriethylammoinium chloride, potassiumiodide, or add phthalic imidine, potassium tert.-butoxide, benzyltriethylammoinium chloride, potassiumiodide, with methyl alcohol, ethanol is solvent, and the mol ratio of benzyltriethylammoinium chloride and raw material is 1:100～1:1, the mol ratio of potassiumiodide and raw material is 1:1000～1:1, (S) mol ratio of epoxy chloropropane and raw material is 10:1～1:1, and temperature of reaction is in the temperature range of 25 ℃～40 ℃ the time, reaction times also is subjected to the volume (ml) of solvent and the impact of the ratio of the quality (g) of raw material.Volume (ml) when solvent: the quality of raw material (g) is 20:1～10:1, reach the reaction yield more than 50%, reaction times need reach more than 110 hours, volume (ml) when solvent: the quality of raw material (g) is 10:1～4:1, can reach the yield more than 50% within the shorter time, volume (ml) when solvent: when the quality of raw material (g) is 4.5:1, and the employing benzyltriethylammoinium chloride is phase-transfer catalyst, reacted 72 hours, and can reach the yield more than 50%.
The present patent application people finds that also phase-transfer catalyst can be selected from benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, three normal-butyl ammoniums, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, chain polyoxyethylene glycol, cyclic crown ether.When take benzyltriethylammoinium chloride as phase-transfer catalyst, than using other phase-transfer catalysts, has the reaction times faster.Under most preferred reaction conditions take Virahol as solvent reaction, the employing benzyltriethylammoinium chloride is phase-transfer catalyst, only need to react the yield that can reach more than 90% in 72 hours, and adopt above-mentioned other phase-transfer catalysts, under equal conditions need to react the yield that just can reach more than 100 hours more than 90%.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.But these embodiment only limit to illustrate the present invention rather than to the further restriction of protection scope of the present invention.
Embodiment 1
Add 85g(0.46 mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046 mol), potassiumiodide 0.76g (0.0046 mol), Virahol 382.5ml, stir, at 28 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 72 hours under the temperature condition of 28 ℃, suction filtration, washing, drying gets solid 88.1g at last, yield 94.5%, purity 92%.
Embodiment 2
Add 85g(0.46 mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046 mol), potassiumiodide 0.76g (0.0046 mol), Virahol 382.5ml, stir, at 32 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 72 hours under the temperature condition of 32 ℃, suction filtration, washing, drying gets solid 87.7g at last, yield 94.0%, purity 90%.
Embodiment 3
Add 85g(0.46 mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046 mol), potassiumiodide 0.76g (0.0046 mol), Virahol 850ml, stir, at 30 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 110 hours under the temperature condition of 30 ℃, suction filtration, washing, drying gets solid 85.4g at last, yield 91.5%, purity 89%.
Embodiment 4
Add 85g(0.46 mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046 mol), potassiumiodide 0.76g (0.0046 mol), Virahol 340ml, stir, at 25 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 110 hours under the temperature condition of 25 ℃, suction filtration, washing, drying gets solid 78.8g at last, yield 84.5%, purity 86.5%.
Embodiment 5
Add 85g(0.46 mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046 mol), potassiumiodide 0.76g (0.0046 mol), Virahol 255ml, stir, at 40 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 72 hours under the temperature condition of 40 ℃, suction filtration, washing, drying gets solid 71.1g at last, yield 76.2%, degree 80.3%.
Embodiment 6
Add 85g (0.46 mol) potassium phthalimide in 1L single port bottle, benzyltriethylammoinium chloride 21g (0.092 mol), potassiumiodide 3.8g (0.023 mol), Virahol 425ml, stir, at 30 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 72 hours under the temperature condition of 30 ℃, suction filtration, washing, drying gets solid 78.8g at last, yield 84.5%, purity 89.2%.
Embodiment 7
Add 85g(0.46mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 5.24g (0.023 mol), potassiumiodide 0.38g (0.0023mol), Virahol 425ml, stir, at 30 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 72 hours under the temperature condition of 30 ℃, suction filtration, washing, drying gets solid 75.8g at last, yield 81.2%, purity 87.6%.
Embodiment 8
Add 85g(0.46mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 105g(0.46 mol), potassiumiodide 0.76g (0.0046 mol), Virahol 425ml(5:1), stir, at 25 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 110 hours under the temperature condition of 25 ℃, suction filtration, washing, drying gets solid 74.5g at last, yield 79.8%, purity 89.3%.
Embodiment 9
Add 85g(0.46mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 1.05g(0.0046 mol), potassiumiodide 0.76g (0.0046 mol), Virahol 425ml(5:1), stir, at 30 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 72 hours under the temperature condition of 30 ℃, suction filtration, washing, drying gets solid 68.3g at last, yield 73.2%, purity 86.7%.
Embodiment 10
Add 85g(0.46mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046 mol), potassiumiodide 76.4g (0.46 mol), Virahol 425ml(5:1), stir, at 25 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 72 hours under the temperature condition of 25 ℃, suction filtration, washing, drying gets solid 82.6g at last, yield 88.5%, purity 89.7%.
Embodiment 11
Add 85g(0.46mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046 mol), potassiumiodide 0.076g (0.00046 mol), methyl alcohol 425ml(5:1), stir, at 35 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 72 hours under the temperature condition of 35 ℃, suction filtration, washing, drying gets solid 49g at last, yield 52.6%, purity 84.4%.
Embodiment 12
Add 85g(0.46mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046 mol), potassiumiodide 0.76g (0.0046 mol), ethanol 425ml(5:1), stir, at 35 ℃, add (S) epoxy chloropropane 42.8g (0.465 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 72 hours under the temperature condition of 35 ℃, suction filtration, washing, drying gets solid 58.4g at last, yield 62.6%, purity 81.3%
Embodiment 13
Add 85g(0.46mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046 mol), potassiumiodide 0.76g (0.0046 mol), ethanol 425ml(5:1), stir, at 29 ℃, add (S) epoxy chloropropane 213.9g (2.312 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 72 hours under the temperature condition of 29 ℃, suction filtration, washing, drying gets solid 60.4g at last, yield 64.7%, purity 87.8%
Embodiment 14
Add 85g(0.46mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046 mol), potassiumiodide 0.76g (0.0046 mol), Virahol 425ml(5:1), stir, at 25 ℃, add (S) epoxy chloropropane 427.8g (4.6 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 72 hours under the temperature condition of 25 ℃, suction filtration, washing, drying gets solid 82.7g at last, yield 88.6%, purity 88.9%
Embodiment 15
Add 85g(0.46mol in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046 mol), potassiumiodide 0.76g (0.0046 mol), Virahol 1700ml(20:1), stir, at 30 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 130 hours under the temperature condition of 30 ℃, suction filtration, washing, drying gets solid 50.6g at last, yield 54.2%, purity 87.6%.
Embodiment 16
Add 85g(0.46mol in 1L single port bottle) potassium phthalimide, three normal-butyl ammonium 8.5g (0.046mol), potassiumiodide 0.76g (0.0046 mol), Virahol 383ml, stir, at 28 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 120 hours under the temperature condition of 28 ℃, suction filtration, washing, drying gets solid 80.9g at last, yield 86.7%, purity 83.2%.
Embodiment 17
Add 85g(0.46mol in 1L single port bottle) potassium phthalimide, Tetrabutyl amonium bromide 18.5g (0.0575mol), potassiumiodide 0.76g (0.0046 mol), Virahol 255ml, stir, at 35 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 140 hours under the condition of 35 ℃, suction filtration, washing, drying gets solid 65.5g at last, yield 70.2%, purity 86.7%.
Embodiment 18
Add 85g(0.46 mol in 1L single port bottle) potassium phthalimide, tri-n-octyl methyl ammonium chloride 3.7g (0.0092mol), potassiumiodide 0.76g (0.0046 mol), Virahol 595ml, stir, at 28 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 130 hours under the temperature condition of 28 ℃, suction filtration, washing, drying gets solid 67.5g at last, yield 72.3%, purity 83.1%.
Embodiment 19
Add 85g(0.46 mol in 1L single port bottle) potassium phthalimide, tetradecyl trimethyl ammonium chloride 8.8g(0.03 mol), potassiumiodide 0.76g (0.0046 mol), methyl alcohol 382.5ml, stir, at 29 ℃, add (S) epoxy chloropropane 128.4g (1.39 mol) in the situation downhill reaction system that stirs, system becomes faint yellow muddiness by white opacity, and reaction is 72 hours under the temperature condition of 29 ℃, suction filtration, washing, drying gets solid 75.0g at last, yield 80.3%, purity 87.4%.
Embodiment 20
Add 67.7g(0.46 mol in 1L single port bottle) phthalic imidine, potassium tert.-butoxide 61.9g, benzyltriethylammoinium chloride 10.5g(0.046 mol), potassiumiodide 0.76g (0.0046 mol), Virahol 382.5ml, stir, at 28 ℃, add (S) epoxy chloropropane 85.6g (0.93 mol) in the situation downhill reaction system of stirring, system becomes faint yellow muddiness by white opacity, reaction is 72 hours under the temperature condition of 28 ℃, suction filtration, washing, dry, get at last solid 84.5g, yield 90.5%, purity 92%.
Synthesizing of embodiment 21 Linezolids
with 40g S-Racemic glycidol phthalic imidine and 39g 3-fluoro-4-(4-morpholinyl) aniline is dissolved in the 400ml dimethyl formamide, reflux 5 hours, cooling, add 2 premium on currency washings, suction filtration, obtain the 60g solid product, again this product is dissolved in the 600ml methylene dichloride, add 32g N, N-carbonyl and imidazoles (CDI), under room temperature, stirring reaction is 20 hours, washing, steam methylene dichloride, obtain the 48g solid product, above-mentioned solid product 40g and 26g hydrazine hydrate are dissolved in 240ml methyl alcohol, reflux 1 hour, be cooled to room temperature, system is with the 300ml dichloromethane extraction, organic phase is washed with 100ml, solvent distillation, obtain the 20g solid product, above-mentioned solid product is dissolved in 200ml toluene, stirred 15 minutes, the 20g acetic anhydride is splashed in reaction system, stirring at room is reacted 1 hour to reacting completely, system is down to 0-5 ℃, suction filtration, with the 200ml recrystallizing methanol, obtain Linezolid solid 16g.
Synthesizing of embodiment 22 razaxabans
Add 5.37g 4-(4 aminophenyl)-3-morpholone mai in the 250ml reaction flask, 5.68g S-Racemic glycidol phthalic imidine, 140ml alcohol-water (V:V=9:1), temperature rising reflux 12 hours, filter, the filter cake washing with alcohol, drying gets solid 7.50g, the mother liquor concentrating under reduced pressure, add 5.68g S-Racemic glycidol phthalic imidine, 140ml alcohol-water (V:V=9:1), temperature rising reflux 13 hours.Filter, the filter cake washing with alcohol, the dry solid 2.80g that gets obtains white solid 10.30g altogether.The 5.23g that gets in above-mentioned white solid adds in the 100ml reaction flask, then adds 20mlN, dinethylformamide, and 4.29gN, N-carbonyl and imidazoles (CDI), the 100 ℃ of stirrings that heat up, TLC monitors reaction process, reacts completely in 6 hours.Add 100ml water, agitation and filtration, drying, get white solid 5.08g, the 4.45g in this 5.08g white solid is dropped in the 250ml reaction flask, add 100ml ethanol, drip the 10ml40% aqueous methylamine solution, temperature rising reflux, evaporated under reduced pressure solvent after 1 hour, add the 50ml tetrahydrofuran (THF), stir, 0-5 ℃ adds the 1.92g triethylamine, drip 2.30g5-chlorothiophene-2-formyl chloride, dropwised stirring at room in 5 minutes, TLC monitors reaction process, and afterreaction was complete in 2 hours.The evaporated under reduced pressure solvent gets white solid, adds 50ml water to stir, filter, and the filter cake washing with alcohol, drying, getting white solid is razaxaban 3.41g.
Claims (10)
1. the preparation method of a S-Racemic glycidol phthalic imidine is characterized in that potassium phthalimide or phthalic imidine and (S) in the reaction of epoxy chloropropane, has added phase-transfer catalyst and potassiumiodide.
2. the preparation method of S-Racemic glycidol phthalic imidine according to claim 1, the mol ratio that it is characterized in that described potassiumiodide and potassium phthalimide or phthalic imidine is 1:1000～1:1, be preferably 1:200～1:20, most preferably be 1:100.
3. the preparation method of S-Racemic glycidol phthalic imidine according to claim 1, the mol ratio that it is characterized in that described phase-transfer catalyst and potassium phthalimide or phthalic imidine is 1:100～1:1, be preferably 1:20～1:5, most preferably be 1:10.
4. the preparation method of S-Racemic glycidol phthalic imidine according to claim 1, the mol ratio that it is characterized in that described (S) epoxy chloropropane and potassium phthalimide or phthalic imidine is 10:1～1:1, be preferably 5:1～1:1, most preferably be 2:1.
5. the preparation method of S-Racemic glycidol phthalic imidine according to claim 1, it is characterized in that described phase-transfer catalyst is one or more in benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, three normal-butyl ammoniums, tetrabutylammonium chloride, 4-butyl ammonium hydrogen sulfate, tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, tetradecyl trimethyl ammonium chloride, chain polyoxyethylene glycol, cyclic crown ether, is preferably benzyltriethylammoinium chloride.
6. the preparation method of the described S-Racemic glycidol of any one phthalic imidine according to claim 1-5, it is characterized in that comprising following reactions steps: add potassium phthalimide, phase-transfer catalyst, potassiumiodide, solvent in reactor, or add phthalic imidine, potassium tert.-butoxide, phase-transfer catalyst, potassiumiodide, solvent in reactor, add (S) epoxy chloropropane in the temperature range of 25 ℃～40 ℃, and in the temperature range of 25 ℃～40 ℃ stirring reaction.
7. the preparation method of S-Racemic glycidol phthalic imidine according to claim 6, is characterized in that adding (S) epoxy chloropropane in the temperature range of 28 ℃～32 ℃, and in the temperature range of 28 ℃～32 ℃ stirring reaction.
8. the preparation method of S-Racemic glycidol phthalic imidine according to claim 6, is characterized in that described solvent is one or more in methyl alcohol, ethanol and Virahol, is preferably Virahol.
9. the preparation method of according to claim 6 or 8 described S-Racemic glycidol phthalic imidines, it is characterized in that described solvent and the volume mass ratio of potassium phthalimide or phthalic imidine are 20:1～3:1, be preferably 10:1～4:1, most preferably be 4.5:1.
10. the preparation method by any one in claim 1-10 makes S-Racemic glycidol phthalic imidine, the application in the Oxazolidinone derivative such as synthetic Linezolid or razaxaban or other heterogeneous ring compounds.
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