CN103382200B - A kind of preparation method of S-Racemic glycidol phthalic imidine - Google Patents
A kind of preparation method of S-Racemic glycidol phthalic imidine Download PDFInfo
- Publication number
- CN103382200B CN103382200B CN201210130995.4A CN201210130995A CN103382200B CN 103382200 B CN103382200 B CN 103382200B CN 201210130995 A CN201210130995 A CN 201210130995A CN 103382200 B CN103382200 B CN 103382200B
- Authority
- CN
- China
- Prior art keywords
- phthalic imidine
- yield
- reaction
- potassiumiodide
- potassium phthalimide
- 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.)
- Active
Links
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims description 16
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims abstract description 117
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- 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 41
- 235000007715 potassium iodide Nutrition 0.000 claims abstract description 39
- 229960004839 potassium iodide Drugs 0.000 claims abstract description 39
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000000034 method Methods 0.000 claims abstract description 11
- 238000003756 stirring Methods 0.000 claims description 34
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 33
- 239000007787 solid Substances 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 29
- 238000005406 washing Methods 0.000 claims description 27
- 238000000967 suction filtration Methods 0.000 claims description 26
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 4
- 239000003444 phase transfer catalyst Substances 0.000 abstract description 23
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000010189 synthetic method Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000002994 raw material Substances 0.000 description 30
- 239000002904 solvent Substances 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-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
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- -1 amide compound Chemical class 0.000 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 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 description 5
- 229960003907 linezolid Drugs 0.000 description 5
- 229950010535 razaxaban Drugs 0.000 description 5
- 230000035484 reaction time Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000012265 solid product Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 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
- 229920003171 Poly (ethylene oxide) Polymers 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
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 3
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 description 3
- 230000000630 rising effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- CEYYIKYYFSTQRU-UHFFFAOYSA-M trimethyl(tetradecyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)C CEYYIKYYFSTQRU-UHFFFAOYSA-M 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
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- AJSHDAOMUKXVDC-UHFFFAOYSA-N butan-1-amine;sulfuric acid Chemical compound CCCC[NH3+].OS([O-])(=O)=O AJSHDAOMUKXVDC-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- DDXLVDQZPFLQMZ-UHFFFAOYSA-M dodecyl(trimethyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCC[N+](C)(C)C DDXLVDQZPFLQMZ-UHFFFAOYSA-M 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
- 238000011160 research Methods 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
- 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
- 238000013019 agitation Methods 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 238000013459 approach Methods 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
- 238000009776 industrial production Methods 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
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-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
- 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
Landscapes
- Indole Compounds (AREA)
Abstract
The present invention relates to a kind of in the reaction of potassium phthalimide or phthalic imidine and (S) epoxy chloropropane, add phase-transfer catalyst and potassiumiodide to synthesize the novel method of S-Racemic glycidol phthalic imidine.This synthetic method can than the yield of prior art very big raising gained S-Racemic glycidol phthalic imidine product, and easy and simple to handle, technical process is simple, safety, and product purity is high, cost is low, is extremely applicable to suitability for industrialized production S-Racemic glycidol phthalic imidine.
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 preparing the oxazolidinones such as new antibiotic Linezolid, new oral anticoagulant razaxaban, also be preparation antimycotic sulfo-oxazolidone, oxazolidinedione simultaneously, as the amide compound of growth hormone secretagogues, be used for the treatment of the important intermediate of the heterogeneous ring compounds such as the morpholine urea derivatives of inflammation.
The preparation method of S-Racemic glycidol phthalic imidine normally adopts the people such as A.Gutcait at TetrahedronAsym.1996, and 7, the method synthesis described in 1641.The method is with phthalic imidine and (S) epoxy chloropropane for raw material, at diethylazodicarboxylate (DEAD) and triphenyl phosphine (PH
3p) under existence, make solvent with tetrahydrofuran (THF), react in the temperature range of 20 DEG C ~ 25 DEG C and obtain for 18 hours, but this reaction generates the by product of more difficulty removing, and reaction yield is lower, yield only about 30%, purity only 60%, not only aftertreatment is loaded down with trivial details, and production cost is high.
WO2007074686 disclose a kind of with phthalic imidine and (S) epoxy chloropropane for raw material, potassium tert.-butoxide and three normal-butyl ammoniums deposit in case in Virahol reaction within 24 hours, prepare the method for S-Racemic glycidol phthalic imidine.But this reaction yield in actual tests is only about 30%, and the highest yield is only 36%, purity, about 80%, causes with this method suitability for industrialized production S-Racemic glycidol phthalic imidine cost higher.
It is raw material that EP1403267 discloses with potassium phthalimide, stirring reaction solvent evaporated after 46 hours in the isopropanol solvent of trimethyl benzyl ammonia chloride and epoxy chloropropane, washing, adds the preparation method that ethyl acetate and normal hexane recrystallization obtain S-Racemic glycidol phthalic imidine.But yield is lower in this reaction actual tests, and be only about 30%, purity is about about 70%, cause S-Racemic glycidol phthalic imidine production cost high.
Bogda etc. are at Synlett, Vol.1996.873-974, disclose in Remarkablefastmicrowave-assistedN-AlkylationofPhthalimid eindrymedia a kind of with phthalic imidine and (S) epoxy chloropropane for raw material, under tetrabutylammonium iodide and salt of wormwood exist, in microwave, the method for S-Racemic glycidol phthalic imidine is prepared in reaction.But because microwave reaction is closed system reaction, with certain danger, be only suitable for laboratory synthesis comparatively in a small amount, amplify after producing, 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 applicable to suitability for industrialized production the preparation method of S-Racemic glycidol phthalic imidine, and the S-Racemic glycidol phthalic imidine purity prepared by the method is high, by product becomes very necessary less.
Summary of the invention
An object of the present invention is that in order to provide, a kind of yield is high, by product is few, cost is low, easy and simple to handle, technical process simple, is applicable 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 is specifically included in the reaction of the adjacent potassium phthalimide of raw material or Phthalimide and (S)-epoxy chloropropane, adds 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, is more preferably 1:100.
The mol ratio of phase-transfer catalyst described in such scheme and potassium phthalimide or phthalic imidine is preferably as 1:100 ~ 1:1, is preferably 1:20 ~ 1:5, is 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, is more preferably 2:1.
Phase-transfer catalyst described in such scheme be preferably 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 one or more, most preferably be benzyltriethylammoinium chloride.
The present invention still further provides the preparation method comprising following reactions steps, concrete steps are as follows: add potassium phthalimide, phase-transfer catalyst, potassiumiodide, solvent in a kettle., or add phthalic imidine, potassium tert.-butoxide, phase-transfer catalyst, potassiumiodide, solvent in a kettle., in the temperature range of 25 DEG C ~ 40 DEG C, add (S) epoxy chloropropane, and in the temperature range of 25 DEG C ~ 40 DEG C 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 DEG C ~ 32 DEG C, and in the temperature range of 28 DEG C ~ 32 DEG C 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 ratio (ml/g) of potassium phthalimide or phthalic imidine, is preferably 10:1 ~ 4:1, most preferably is 4.5:1.
Present invention also offers and obtain S-Racemic glycidol phthalic imidine by above-mentioned preparation method, the application in the synthesis Oxazolidinone derivative such as Linezolid or razaxaban or other heterogeneous ring compounds.
Present invention applicant is when adopting (S)-epoxy chloropropane and potassium phthalimide at 30 DEG C, be that stirring solvent is reacted with Virahol, find during to prepare S-Racemic glycidol phthalic imidine, 100 hours are reached when reacted, thin-layer chromatography monitoring reaction is not carried out completely yet, suction filtration, after filtration cakes torrefaction, finds that the S-Racemic glycidol phthalic imidine product yield obtained is only 10%-20%.
Present inventor 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 DEG C, still extremely faint to the raising of reaction yield.
Present inventor is in order to improve yield, improve speed of response, in a kettle. except adding potassium phthalimide, also add potassiumiodide as catalyzer, to improving the reactive behavior of epoxy chloropropane, but when in Virahol, 30 DEG C of reaction times reach 50 hours, and thin-layer chromatography monitoring reaction is not carried out completely yet, suction filtration, after filtration cakes torrefaction, find that the S-Racemic glycidol phthalic imidine product yield obtained is only 10%-20%.
Present inventor again according to the report of WO2007074686 with phthalic imidine and (S) epoxy chloropropane for raw material, find when potassium tert.-butoxide and three normal-butyl ammoniums are deposited and reacted in Virahol and obtain S-Racemic glycidol phthalic imidine in 24 hours in case, document yield can repeat out, the highest yield of test of many times is only 36% in this approach, continue reaction after 48 hours, find that the S-Racemic glycidol phthalic imidine product yield obtained is only about 35%.
In order to improve yield, present inventor attempts substituting three normal-butyl ammoniums with benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, alpha-cylodextrin or chain polyoxyethylene glycol and makes phase-transfer catalyst, with potassium phthalimide and (S) epoxy chloropropane for raw material, in Virahol, 30 DEG C are reacted 48 hours, suction filtration, the highest yield of the S-Racemic glycidol phthalic imidine product obtained after filtration cakes torrefaction is still lower than 40%.
Present invention applicant attempts change reaction solvent to improve reaction yield, with potassium phthalimide and (S) epoxy chloropropane for raw material, deposit at three normal-butyl ammoniums and react 48 hours in ethanol in case, the yield of the S-Racemic glycidol phthalic imidine product obtained is only 26%, react 48 hours in methyl alcohol, the yield of the S-Racemic glycidol phthalic imidine product obtained is 18%.
Present invention applicant attempts consumption using benzyltriethylammoinium chloride as phase-transfer catalyst and is added to maximum, and namely the mol ratio of phase-transfer catalyst and raw material is 1:1, but to the raising of reaction yield also and not obvious.
Present invention applicant is after lot of experiments research, find uncannily, with potassium phthalimide be raw material or with phthalic imidine and potassium tert.-butoxide for raw material, with methyl alcohol, ethanol or Virahol for solvent, when phase-transfer catalyst and potassiumiodide exist simultaneously, the yield of reaction can be made to obtain surprising lifting.
Present invention applicant'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, (S) when the mol ratio of epoxy chloropropane and raw material is 10:1 ~ 1:1, temperature of reaction is in the temperature range of 25 DEG C ~ 40 DEG C, the volume (ml) of solvent: when the quality (g) of raw material is for 20:1 ~ 3:1, the yield of reaction can reach more than 50%, purity is at 80%-95%, when using Virahol as solvent, can obtain than with methyl alcohol, better yield when ethanol is solvent, under the above-described reaction conditions, take Virahol as solvent, yield can reach more than 70%, purity is at 80%-95%.
When adding potassium phthalimide in a kettle., 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, (S) when the mol ratio of epoxy chloropropane and raw material is 5:1 ~ 1:1, temperature of reaction is in the temperature range of 25 DEG C ~ 40 DEG C, the volume (ml) of solvent: when the quality (g) of raw material is for 10:1 ~ 4:1, the yield of reaction can reach more than 60%, purity is at 80%-95%, if using Virahol as solvent, under the above-described reaction conditions, yield can reach more than 80%, purity is at 80%-95%.
Most preferred, when adding potassium phthalimide in a kettle., 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, (S) when the mol ratio of epoxy chloropropane and raw material is 2:1, temperature of reaction is in the temperature range of 28 DEG C ~ 32 DEG C, the volume (ml) of solvent: when the quality (g) of raw material is for 4.5:1, the yield of reaction can reach more than 70%, purity is at 80%-95%, if using Virahol as solvent, under the above-described reaction conditions, yield can reach more than 90%, purity is at 80%-95%.
Present inventor is also known under study for action, when adding potassium phthalimide in a kettle., 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 when temperature of reaction is in the temperature range of 25 DEG C ~ 40 DEG C, reaction times is also by the impact of the volume (ml) of solvent with the ratio of the quality (g) of raw material.Volume (ml) when solvent: the quality (g) of raw material is 20:1 ~ 10:1, reach the reaction yield of more than 50%, reaction times need reach more than 110 hours, volume (ml) when solvent: the quality (g) of raw material is 10:1 ~ 4:1, the yield of more than 50% can be reached within the shorter time, volume (ml) when solvent: when the quality (g) of raw material is for 4.5:1, and adopt benzyltriethylammoinium chloride to be phase-transfer catalyst, react 72 hours, the yield of more than 50% can be reached.
Present invention applicant also finds that 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 taking benzyltriethylammoinium chloride as phase-transfer catalyst, than other phase-transfer catalysts of use, there is the reaction times faster.Be solvent reaction with Virahol under most preferred reaction conditions, employing benzyltriethylammoinium chloride is phase-transfer catalyst, only need reaction that the yield of more than 90% within 72 hours, can be reached, and adopt other phase-transfer catalysts above-mentioned, under equal conditions need reaction more than 100 hours just can reach the yield of more than 90%.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.But these embodiments are only limitted to the present invention instead of the further restriction to protection scope of the present invention are described.
embodiment 1
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046mol), potassiumiodide 0.76g (0.0046mol), Virahol 382.5ml, stir, at 28 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 72 hours under the temperature condition of 28 DEG C, suction filtration, washing, dry, finally obtain solid 88.1g, yield 94.5%, purity 92%.
embodiment 2
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046mol), potassiumiodide 0.76g (0.0046mol), Virahol 382.5ml, stir, at 32 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 72 hours under the temperature condition of 32 DEG C, suction filtration, washing, dry, finally obtain solid 87.7g, yield 94.0%, purity 90%.
embodiment 3
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046mol), potassiumiodide 0.76g (0.0046mol), Virahol 850ml, stir, at 30 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 110 hours under the temperature condition of 30 DEG C, suction filtration, washing, dry, finally obtain solid 85.4g, yield 91.5%, purity 89%.
embodiment 4
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046mol), potassiumiodide 0.76g (0.0046mol), Virahol 340ml, stir, at 25 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 110 hours under the temperature condition of 25 DEG C, suction filtration, washing, dry, finally obtain solid 78.8g, yield 84.5%, purity 86.5%.
embodiment 5
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046mol), potassiumiodide 0.76g (0.0046mol), Virahol 255ml, stir, at 40 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 72 hours under the temperature condition of 40 DEG C, suction filtration, washing, dry, finally obtain solid 71.1g, yield 76.2%, degree 80.3%.
embodiment 6
85g (0.46mol) potassium phthalimide is added in 1L single port bottle, benzyltriethylammoinium chloride 21g (0.092mol), potassiumiodide 3.8g (0.023mol), Virahol 425ml, stir, at 30 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 72 hours under the temperature condition of 30 DEG C, suction filtration, washing, dry, finally obtain solid 78.8g, yield 84.5%, purity 89.2%.
embodiment 7
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 5.24g (0.023mol), potassiumiodide 0.38g (0.0023mol), Virahol 425ml, stir, at 30 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 72 hours under the temperature condition of 30 DEG C, suction filtration, washing, dry, finally obtain solid 75.8g, yield 81.2%, purity 87.6%.
embodiment 8
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 105g(0.46mol), potassiumiodide 0.76g (0.0046mol), Virahol 425ml(5:1), stir, at 25 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 110 hours under the temperature condition of 25 DEG C, suction filtration, washing, dry, finally obtain solid 74.5g, yield 79.8%, purity 89.3%.
embodiment 9
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 1.05g(0.0046mol), potassiumiodide 0.76g (0.0046mol), Virahol 425ml(5:1), stir, at 30 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 72 hours under the temperature condition of 30 DEG C, suction filtration, washing, dry, finally obtain solid 68.3g, yield 73.2%, purity 86.7%.
embodiment 10
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046mol), potassiumiodide 76.4g (0.46mol), Virahol 425ml(5:1), stir, at 25 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 72 hours under the temperature condition of 25 DEG C, suction filtration, washing, dry, finally obtain solid 82.6g, yield 88.5%, purity 89.7%.
embodiment 11
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046mol), potassiumiodide 0.076g (0.00046mol), methyl alcohol 425ml(5:1), stir, at 35 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 72 hours under the temperature condition of 35 DEG C, suction filtration, washing, dry, finally obtain solid 49g, yield 52.6%, purity 84.4%.
embodiment 12
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046mol), potassiumiodide 0.76g (0.0046mol), ethanol 425ml(5:1), stir, at 35 DEG C, add (S) epoxy chloropropane 42.8g (0.465mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 72 hours under the temperature condition of 35 DEG C, suction filtration, washing, dry, finally obtain solid 58.4g, yield 62.6%, purity 81.3%
embodiment 13
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046mol), potassiumiodide 0.76g (0.0046mol), ethanol 425ml(5:1), stir, at 29 DEG C, add (S) epoxy chloropropane 213.9g (2.312mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 72 hours under the temperature condition of 29 DEG C, suction filtration, washing, dry, finally obtain solid 60.4g, yield 64.7%, purity 87.8%
embodiment 14
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046mol), potassiumiodide 0.76g (0.0046mol), Virahol 425ml(5:1), stir, at 25 DEG C, add (S) epoxy chloropropane 427.8g (4.6mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 72 hours under the temperature condition of 25 DEG C, suction filtration, washing, dry, finally obtain solid 82.7g, yield 88.6%, purity 88.9%
embodiment 15
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, benzyltriethylammoinium chloride 10.5g(0.046mol), potassiumiodide 0.76g (0.0046mol), Virahol 1700ml(20:1), stir, at 30 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 130 hours under the temperature condition of 30 DEG C, suction filtration, washing, dry, finally obtain solid 50.6g, yield 54.2%, purity 87.6%.
embodiment 16
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, three normal-butyl ammonium 8.5g (0.046mol), potassiumiodide 0.76g (0.0046mol), Virahol 383ml, stir, at 28 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 120 hours under the temperature condition of 28 DEG C, suction filtration, washing, dry, finally obtain solid 80.9g, yield 86.7%, purity 83.2%.
embodiment 17
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, Tetrabutyl amonium bromide 18.5g (0.0575mol), potassiumiodide 0.76g (0.0046mol), Virahol 255ml, stir, at 35 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 140 hours under the condition of 35 DEG C, suction filtration, washing, dry, finally obtain solid 65.5g, yield 70.2%, purity 86.7%.
embodiment 18
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, tri-n-octyl methyl ammonium chloride 3.7g (0.0092mol), potassiumiodide 0.76g (0.0046mol), Virahol 595ml, stir, at 28 DEG C, add (S) epoxy chloropropane 85.6g (0.93mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 130 hours under the temperature condition of 28 DEG C, suction filtration, washing, dry, finally obtain solid 67.5g, yield 72.3%, purity 83.1%.
embodiment 19
85g(0.46mol is added in 1L single port bottle) potassium phthalimide, tetradecyl trimethyl ammonium chloride 8.8g(0.03mol), potassiumiodide 0.76g (0.0046mol), methyl alcohol 382.5ml, stir, at 29 DEG C, add (S) epoxy chloropropane 128.4g (1.39mol) in the situation downhill reaction system stirred, system becomes faint yellow muddiness from white opacity, reacts 72 hours under the temperature condition of 29 DEG C, suction filtration, washing, dry, finally obtain solid 75.0g, yield 80.3%, purity 87.4%.
embodiment 20
67.7g(0.46mol is added in 1L single port bottle) phthalic imidine, potassium tert.-butoxide 61.9g, benzyltriethylammoinium chloride 10.5g(0.046mol), potassiumiodide 0.76g (0.0046mol), Virahol 382.5ml, stir, at 28 DEG C, in the situation downhill reaction system of stirring, add (S) epoxy chloropropane 85.6g (0.93mol), system becomes faint yellow muddiness from white opacity, react 72 hours under the temperature condition of 28 DEG C, suction filtration, washing, dry, finally obtain solid 84.5g, yield 90.5%, purity 92%.
the synthesis of embodiment 21 Linezolid
By 40gS-Racemic glycidol phthalic imidine and the fluoro-4-(4-morpholinyl of 39g3-) aniline is dissolved in 400ml dimethyl formamide, reflux 5 hours, cooling, add 2 premium on currency washings, suction filtration, obtain 60g solid product, again this product is dissolved in 600ml methylene dichloride, add 32gN, N-carbonyl and imidazoles (CDI), stirred at ambient temperature reacts 20 hours, washing, steam methylene dichloride, obtain 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 300ml dichloromethane extraction, organic phase is washed with 100ml, solvent distillation, obtain 20g solid product, above-mentioned solid product is dissolved in 200ml toluene, stir 15 minutes, by in 20g acetic anhydride instillation reaction system, stirring at room temperature reacts 1 little of reacting completely, system is down to 0-5 DEG C, suction filtration, with 200ml recrystallizing methanol, obtain Linezolid solid 16g.
the synthesis of embodiment 22 razaxaban
5.37g4-(4 aminophenyl)-3-morpholone mai is added in 250ml reaction flask, 5.68gS-Racemic glycidol phthalic imidine, 140ml alcohol-water (V:V=9:1), temperature rising reflux 12 hours, filter, filter cake washing with alcohol, dry, obtain solid 7.50g, mother liquor concentrating under reduced pressure, add 5.68gS-Racemic glycidol phthalic imidine, 140ml alcohol-water (V:V=9:1), temperature rising reflux 13 hours.Filter, filter cake washing with alcohol, dry solid 2.80g, obtains white solid 10.30g altogether.The 5.23g got in above-mentioned white solid adds in 100ml reaction flask, then adds 20mlN, dinethylformamide, 4.29gN, N-carbonyl and imidazoles (CDI), and heat up 100 DEG C of stirrings, and TLC monitors reaction process, within 6 hours, reacts completely.Add 100ml water, agitation and filtration, dry, obtain white solid 5.08g, the 4.45g in this 5.08g white solid is dropped in 250ml reaction flask, adds 100ml ethanol, drip 10ml40% aqueous methylamine solution, temperature rising reflux, evaporated under reduced pressure solvent after 1 hour, add 50ml tetrahydrofuran (THF), stir, 0-5 DEG C adds 1.92g triethylamine, drip 2.30g5-chlorothiophene-2-formyl chloride, within 5 minutes, dropwise, stirring at room temperature, TLC monitors reaction process, reacts completely after 2 hours.Evaporated under reduced pressure solvent, obtains white solid, adds 50ml water and stirs, filter, filter cake washing with alcohol, dry, obtains white solid and razaxaban 3.41g.
Claims (2)
1. the preparation method of a S-Racemic glycidol phthalic imidine, it is characterized in that comprising following reactions steps: add potassium phthalimide, benzyltriethylammoinium chloride, potassiumiodide, Virahol in a kettle., (S) epoxy chloropropane is added in the temperature range of 28 DEG C ~ 32 DEG C, and in the temperature range of 28 DEG C ~ 32 DEG C stirring reaction, suction filtration, washing, dry, finally obtain solid; Wherein Virahol and the volume mass of potassium phthalimide are than being 4.5:1, (S) mol ratio of epoxy chloropropane and potassium phthalimide is 2:1, the mol ratio 1:10 of benzyltriethylammoinium chloride and potassium phthalimide, the mol ratio 1:100 of potassiumiodide and potassium phthalimide.
2. by the method preparing S-Racemic glycidol phthalic imidine according to claim 1, the application in synthesis Oxazolidinone derivative.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210130995.4A CN103382200B (en) | 2012-05-02 | 2012-05-02 | A kind of preparation method of S-Racemic glycidol phthalic imidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210130995.4A CN103382200B (en) | 2012-05-02 | 2012-05-02 | A kind of preparation method of S-Racemic glycidol phthalic imidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103382200A CN103382200A (en) | 2013-11-06 |
| CN103382200B true CN103382200B (en) | 2016-04-20 |
Family
ID=49490151
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210130995.4A Active CN103382200B (en) | 2012-05-02 | 2012-05-02 | A kind of preparation method of S-Racemic glycidol phthalic imidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103382200B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104672217A (en) * | 2013-11-27 | 2015-06-03 | 北京众和民健医药科技有限公司 | New linezolid intermediate, preparation method thereof, and linezolid synthesis method |
| CN104569213A (en) * | 2015-01-23 | 2015-04-29 | 江苏正大清江制药有限公司 | Method for measuring content of (S)-(+)-N-(2,3-ethyoxyl propyl) phthalimide by adopting high performance liquid chromatography |
| CN108440383B (en) * | 2018-04-03 | 2020-02-21 | 浙江永太科技股份有限公司 | Preparation method of rivaroxaban intermediate |
| CN110885325B (en) * | 2018-09-11 | 2021-09-07 | 新发药业有限公司 | Preparation method of (S) -glycidol phthalimide |
| CN109970643A (en) * | 2019-04-19 | 2019-07-05 | 哈尔滨工业大学（威海） | A kind of green synthesis method of tetrahydroacridine compound under the promotion of iodine anion |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1403267A1 (en) * | 2002-09-25 | 2004-03-31 | Daiso Co., Ltd. | Process for preparing glycidylphthalimide |
| CN1660744A (en) * | 2004-12-08 | 2005-08-31 | 嘉兴学院 | Method for synthesizing dichloroaryl ether with dichlorophenol and chloroalkane |
| CN102050767A (en) * | 2009-11-11 | 2011-05-11 | 江苏傲伦达科技实业股份有限公司 | Preparation method of 1,1'-sulfonyl bis(4-(2-propylene)oxy benzene) |
| CN102180887A (en) * | 2011-03-15 | 2011-09-14 | 江苏大学 | Method for synthesizing 2,5-diethyl phthalate-3,4-ethylene dioxythiophene |
| CN102311400A (en) * | 2010-06-29 | 2012-01-11 | 翔真生物科技股份有限公司 | Method for preparing 5-L-aminomethyl-3-aryl-2-oxazolidinones |
-
2012
- 2012-05-02 CN CN201210130995.4A patent/CN103382200B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1403267A1 (en) * | 2002-09-25 | 2004-03-31 | Daiso Co., Ltd. | Process for preparing glycidylphthalimide |
| CN1660744A (en) * | 2004-12-08 | 2005-08-31 | 嘉兴学院 | Method for synthesizing dichloroaryl ether with dichlorophenol and chloroalkane |
| CN102050767A (en) * | 2009-11-11 | 2011-05-11 | 江苏傲伦达科技实业股份有限公司 | Preparation method of 1,1'-sulfonyl bis(4-(2-propylene)oxy benzene) |
| CN102311400A (en) * | 2010-06-29 | 2012-01-11 | 翔真生物科技股份有限公司 | Method for preparing 5-L-aminomethyl-3-aryl-2-oxazolidinones |
| CN102180887A (en) * | 2011-03-15 | 2011-09-14 | 江苏大学 | Method for synthesizing 2,5-diethyl phthalate-3,4-ethylene dioxythiophene |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103382200A (en) | 2013-11-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103382200B (en) | A kind of preparation method of S-Racemic glycidol phthalic imidine | |
| CN104130258B (en) | The method for transformation of a kind of dimer | |
| CN113880774B (en) | Preparation method of phenyl isoxazoline compound | |
| US20100249439A1 (en) | Process for controlled crystal size in 1,2-substituted 3,4-dioxo-1-cyclobutene compounds | |
| JP2019081758A (en) | Method for preparing azoxystrobin | |
| CN102180842B (en) | Synthesis method of 2-amino-delta 2-thiazoline-4-carboxylic acid | |
| CN112062712A (en) | Preparation method of 2- (5-bromo-3-methylpyridin-2-yl) acetic acid hydrochloride | |
| CN104530033A (en) | Novel process method for preparing arotinolol hydrochloride | |
| CN102267961A (en) | Method for preparing ethyl (3R,4R,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-1-cyclohexene-1-formate | |
| CN112920079A (en) | Preparation method of amide compound | |
| CN107365325A (en) | A kind of purity is high, the production method of the N of high income, O-bis- (trimethylsilyls) acetamide | |
| CN114213308A (en) | Method for synthesizing atorvastatin ester by using continuous flow tubular reactor | |
| CN113651722A (en) | Synthesis method of 1- (3-hydroxyphenyl) -1,3, 3-trimethyl urea, intermediate and application thereof | |
| CN110003083B (en) | Process method for preparing S-indoline-2-carboxylic acid by using Ir catalyst | |
| CN103333180A (en) | Preparation method of aspoxicillin | |
| CN110066233B (en) | Preparation method of mono-substituted amine compound | |
| CN101914061A (en) | Preparation method of 2-phenyl-(4)5-hydroxymethyl imidazoles compound | |
| CN102234239A (en) | Optimization process of glycine ethyl ester hydrochloride | |
| CN111943931B (en) | Preparation method of pymetrozine | |
| CN103351348A (en) | Synthetic method for 2-methylamino pyrimidine hydrochloride | |
| CN115919817B (en) | Gediselenium compounds and their synthesis methods and applications | |
| CN106316861B (en) | A kind of method for preparing double benzene bacterium amine | |
| CN114213323B (en) | New process for synthesizing procaterol hydrochloride | |
| CN114437052B (en) | Method for synthesizing statin drug intermediate by using continuous flow micro-channel reactor | |
| WO2024152408A1 (en) | Alkylzinc reagent, and preparation method therefor and use thereof |
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 | ||
| CP03 | Change of name, title or address |
Address after: 610041, No. 2, building 4, No. 201, building C, nine Hing Road, 6 hi tech Zone, Sichuan, Chengdu, 402 Patentee after: Chengdu state bio medicine Co., Ltd. Address before: 610041 Sichuan Province, Chengdu hi tech Zone, No. nine Hing Road, building C, No. 6, building No. 2, No. 201 Patentee before: Chengdu Guohong Medicine Co., Ltd. |
|
| CP03 | Change of name, title or address |