CN102351810A - Resolution method of levocetirizine chiral intermediates - Google Patents
Resolution method of levocetirizine chiral intermediates Download PDFInfo
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- CN102351810A CN102351810A CN2011102350256A CN201110235025A CN102351810A CN 102351810 A CN102351810 A CN 102351810A CN 2011102350256 A CN2011102350256 A CN 2011102350256A CN 201110235025 A CN201110235025 A CN 201110235025A CN 102351810 A CN102351810 A CN 102351810A
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- levocetirizine
- chiral
- splitting
- ionic liquid
- toluene
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- 238000000034 method Methods 0.000 title claims abstract description 31
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 title claims abstract description 30
- 229960001508 levocetirizine Drugs 0.000 title claims abstract description 30
- 239000000543 intermediate Substances 0.000 title abstract description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 97
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 239000002608 ionic liquid Substances 0.000 claims abstract description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 34
- -1 4-chloro-phenyl- Chemical group 0.000 claims description 25
- 239000000047 product Substances 0.000 claims description 11
- 230000006340 racemization Effects 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 7
- 230000008025 crystallization Effects 0.000 claims description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 7
- 150000002500 ions Chemical class 0.000 claims description 5
- 229960002510 mandelic acid Drugs 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-ZILXKATJSA-N (3R)-2,3-dihydroxybutanedioic acid Chemical compound OC([C@@H](O)C(O)=O)C(O)=O FEWJPZIEWOKRBE-ZILXKATJSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 239000013078 crystal Substances 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 abstract description 9
- 238000005516 engineering process Methods 0.000 abstract description 6
- 238000002844 melting Methods 0.000 abstract description 3
- 230000008018 melting Effects 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- UZKBSZSTDQSMDR-UHFFFAOYSA-N 1-[(4-chlorophenyl)-phenylmethyl]piperazine Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)N1CCNCC1 UZKBSZSTDQSMDR-UHFFFAOYSA-N 0.000 abstract 1
- 239000008346 aqueous phase Substances 0.000 abstract 1
- 238000003889 chemical engineering Methods 0.000 abstract 1
- 238000000605 extraction Methods 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N Lactic Acid Natural products CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000001387 anti-histamine Effects 0.000 description 3
- 239000000739 antihistaminic agent Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005194 fractionation Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- PGLIUCLTXOYQMV-GHVWMZMZSA-N 2-[2-[4-[(r)-(4-chlorophenyl)-phenylmethyl]piperazine-1,4-diium-1-yl]ethoxy]acetic acid;dichloride Chemical compound Cl.Cl.C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 PGLIUCLTXOYQMV-GHVWMZMZSA-N 0.000 description 1
- SZIFAVKTNFCBPC-UHFFFAOYSA-N 2-chloroethanol Chemical compound OCCCl SZIFAVKTNFCBPC-UHFFFAOYSA-N 0.000 description 1
- IWEYZXWPWNBRLG-UHFFFAOYSA-N 2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(N)(=O)=O IWEYZXWPWNBRLG-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- ADJAKLLLVKVHGL-UHFFFAOYSA-N N-(chloromethyl)-N-phenylaniline Chemical compound C1(=CC=CC=C1)N(C1=CC=CC=C1)CCl ADJAKLLLVKVHGL-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 206010039094 Rhinitis perennial Diseases 0.000 description 1
- 208000036284 Rhinitis seasonal Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000006011 chloroethoxy group Chemical group 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940088529 claritin Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000000938 histamine H1 antagonist Substances 0.000 description 1
- FAHBNUUHRFUEAI-UHFFFAOYSA-M hydroxidooxidoaluminium Chemical compound O[Al]=O FAHBNUUHRFUEAI-UHFFFAOYSA-M 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 1
- 229910001412 inorganic anion Inorganic materials 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 229960003308 levocetirizine dihydrochloride Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000005838 radical anions Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 208000017022 seasonal allergic rhinitis Diseases 0.000 description 1
- FDRCDNZGSXJAFP-UHFFFAOYSA-M sodium chloroacetate Chemical compound [Na+].[O-]C(=O)CCl FDRCDNZGSXJAFP-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A resolution method of a levocetirizine chiral intermediates belongs to the technical field of fine organic chemical engineering. The method comprises the following specific steps: adding racemic 1-[(4-chlorophenyl)benzyl]piperazine and chiral ionic liquid in a reaction container to react at 10-100 DEG C for 1-10 hours, extracting with toluene for layering, adjusting the pH value of the aqueous phase with 10wt% of sodium hydroxide solution to 11-12, extracting with toluene again, and concentrating to crystallize after the post-treatment, thus obtaining the product. The chiral ionic liquid is used as the solvent and resolving agent, the technology is easy to operate, the efficiency is high, the yield of three wastes is low, the yield of the product is more than 34%, the melting range of the product is narrow, the melting point is 94-96 DEG C, the specific rotation [alpha] D is not more than -21.5 degrees (C1, toluene), the optical purity is not less than 99.0%, and the content is not less than 99.0%. The post-treatment is convenient, the ionic liquid can be used repeatedly and the resolution method is an economical, practical, green and environmentally friendly technology.
Description
Technical field
The present invention relates to a kind of method for splitting that utilizes chiral ionic liquid to carry out the levocetirizine chiral intermediate.
Background technology
Levocetirizine dihydrochloride is a third generation antihistaminic; It is the single optical isomer of s-generation antihistaminic cetirizine; Be selectivity H1 receptor antagonist; Treatment seasonal allergic rhinitis by U.S. SePracor company and the joint development of Belgian UCB. S.A. (BE) Bruxelles Belgium; Perennial rhinitis, the smoked a kind of new chiral drug of measles of adult and juvenile chronic idiopathic.Anti-allergic effects is rapid-action, strong and lasting, and drug effect is better than existing all antihistaminics, does not have central nervous system side effects such as calm, drowsiness, is Claritin of new generation.Nineteen eighty-two, UCB. S.A. (BE) Bruxelles Belgium report by 1-[(4-chloro-phenyl-) phenmethyl] piperazine and the condensation of chloroethoxy methyl acetate, hydrolysis then, salify obtains 2-[2-[4-[(4-chloro-phenyl-) phenmethyl]-the 1-piperazinyl] oxyethyl group]-acetic acid hydrochloride.People such as nineteen ninety Cossement E have reported the phenmethyl by 1-[(4-chloro-phenyl-)] piperazine and the condensation of chloroethoxy second eyeball, hydrolysis then, salify obtains 2-[2-[4-[(4-chloro-phenyl-) phenmethyl]-the 1-piperazinyl] oxyethyl group]-acetic acid hydrochloride.Reported simultaneously phenmethyl again by 1-[(4-chloro-phenyl-)] piperazine and chloroethanol condensation, direct then and sodium chloroacetate reaction obtains 2-[2-[4-[(4-chloro-phenyl-) phenmethyl with the hcl acidifying salify at last]-the 1-piperazinyl] oxyethyl group]-acetic acid hydrochloride.Then through splitting intermediate 1-[(4-chloro-phenyl-) phenmethyl with L-(+) tartrate] piperazine, obtained left-handed cetrizine hcl.But resolution yield only is 14.9%, and optical purity is lower.2002, Derk, people such as A. reported with phenyl aldehyde and isobutyl-sulphonamide at Ti (OEt)
4Effect reaction down, and then carry out grignard reaction, with splitting, obtain compound (1) with L-(+) tartrate.Under hydrochloric acid and methyl alcohol effect, obtain then the chlorodiphenyl methylamine, cyclization, acidifying obtains LEVO CITRAZINE.2005, people such as Wang Yuling were raw material with the Benzoyl chloride, and through acidylate, reduction splits with L-(+) tartrate, cyclization then, and reactions such as acidolysis make LEVO CITRAZINE.
Ionic liquid has caused people's attention as a kind of novel green replace solvents, has been widely used in organic synthesis industry.Ionic liquid is the fluid cpds of being made up of ion fully, is that low temperature is also referred to as watery fusion salt less than the salt that is in a liquid state under 100 oC, generally is made up of organic cation and inorganic anion.Studying more ionic liquid normally is made up of di-alkyl-imidazole or alkyl pyridine quaternary ammonium cation and acid radical anions such as Tetrafluoroboric acid, phosphofluoric acid and chlorine aluminic acid.Ionic liquid compare with organic solvent have non-volatile, nonflammable explosive, be difficult for oxidation; Have higher thermostability, organism and inorganics are had good solubility, reaction can be carried out at homogeneous phase; It is easily separated that after product is accomplished in reaction, and ionic liquid can be recycled.Simultaneously, ionic liquid can change the mechanism of reaction again, causes new catalytic activity, improves the selectivity of transformation efficiency and reaction.Chiral ionic liquid is the ionic liquid that utilizes chirality positively charged ion or chirality negatively charged ion to make, and chiral ionic liquid has the dual-functionality of chiral material and fluent material.Therefore, the fractionation that utilizes chiral ionic liquid to carry out the levocetirizine chiral intermediate has broad application prospects, but does not also similarly report both at home and abroad at present.
Summary of the invention
To the problems referred to above that exist in the prior art, the object of the present invention is to provide a kind of fractionation that utilizes chiral ionic liquid to carry out the levocetirizine chiral intermediate, be energy-saving and emission-reduction, Sustainable development, recycling economy and eco-friendly utilisation technology.
The method for splitting of described a kind of levocetirizine chiral intermediate is characterized in that described method for splitting comprises the steps:
1) described levocetirizine chiral intermediate is (R)-1-[(4-chloro-phenyl-) phenmethyl] piperazine, the structural formula of described levocetirizine chiral intermediate and chiral ionic liquid is shown in formula I, formula II:
（Ⅰ） （Ⅱ）
2) with 1-[(4-chloro-phenyl-) phenmethyl of racemization] piperazine and the chiral ionic liquid shown in formula II join in the reaction vessel together; Reacted 1-10 hour down in 10-100 ℃ temperature condition; Reaction finishes the back extracted in toluene; Layering; Toluene layer is used for racemization, and water is for further processing;
3) with step 2) in the water that obtains to use mass percent concentration be that 10% sodium hydroxide solution transfers to pH to 11-12, use extracted in toluene again, obtain as 1 through condensing crystal after the aftertreatment) in the product shown in the formula I.
The method for splitting of described a kind of levocetirizine chiral intermediate is characterized in that R is the substituted alkyl of C1-C10 in the described chiral ionic liquid, described negatively charged ion L
-Alcohol acid is a R-lactic acid, any one in R-tartrate or the R-amygdalic acid.
The method for splitting of described a kind of levocetirizine chiral intermediate is characterized in that step 2) described in temperature of reaction be 30-60 ℃.
The method for splitting of described a kind of levocetirizine chiral intermediate is characterized in that step 2) described in reaction times be 3-6 hour.
The method for splitting of described a kind of levocetirizine chiral intermediate is characterized in that step 2) 1-[(4-chloro-phenyl-) phenmethyl of described racemization] molar ratio of piperazine and chiral ionic liquid is 1:2-3.
The method for splitting of described a kind of levocetirizine chiral intermediate; It is characterized in that the described post-treating method of step 3) is following: the toluene layer after the extracted in toluene is dry earlier; The evaporated under reduced pressure solvent obtains crude product again, with the normal hexane crystallization must be shown in formula I product.
The method for splitting of described a kind of levocetirizine chiral intermediate, it is characterized in that described chiral ionic liquid wherein R be the substituted alkyl of C1-C6, alcohol acid L
-Be the R-amygdalic acid.
The method for splitting of described a kind of levocetirizine chiral intermediate is characterized in that step 2) described in temperature of reaction be 40-50 ℃.
The method for splitting of described a kind of levocetirizine chiral intermediate is characterized in that step 2) described in reaction times be 4-5 hour.
The method for splitting of described a kind of levocetirizine chiral intermediate is characterized in that step 2) 1-[(4-chloro-phenyl-) phenmethyl of described racemization] molar ratio of piperazine and chiral ionic liquid is 1:2.
Through adopting above-mentioned technology, compared with prior art, beneficial effect of the present invention is following:
As solvent and resolving agent, this technology is easy to operate with chiral ionic liquid in the present invention, excellent in efficiency, and the three wastes are few, and yield is greater than 34%, and the product melting range is short, and fusing point is 94-96 ℃, specific rotatory power: [α]
D≤-21.5 ° (C1, toluene), optical purity:>=99.0%, content:>=99.0%.Convenient post-treatment, ionic liquid is reusable, is economical and practical green environmental protection technique.
Embodiment
Below in conjunction with specific embodiment the present invention is described further, but protection scope of the present invention is not limited to this.
Embodiment 1
With 1-[(4-chloro-phenyl-) phenmethyl] piperazine 287 restrains (1 mole) and chirality tartrate ionic liquid joins in the reaction vessel for 3 moles together; In 50 ℃ of reactions 5 hours; With 200 milliliters of extractions of toluene; Reaction system after the extraction transfers to pH=11-12 with 10% sodium hydroxide solution; Again with three extractions of 200 milliliters of branches of toluene; Combining methylbenzene solution; Anhydrous sodium sulfate drying; Filter; Concentrate, the normal hexane crystallization gets white crystalline powder product 52 grams, yield 36%; Fusing point: 94～96 ℃, specific rotatory power: [α]
D≤-21.5 ° (C1, toluene), optical purity:>=99.0%, content:>=99.0%.
Embodiment 2
With 1-[(4-chloro-phenyl-) phenmethyl] piperazine 287 restrains (1 mole) and chirality lactic acid ion liquid joins in the reaction vessel for 1 mole together; In 10 ℃ of reactions 10 hours; With 200 milliliters of extractions of toluene; It is that 10% sodium hydroxide transfers to pH=11-12 that reaction system after the extraction is used mass percentage concentration; Again with three extractions of 200 milliliters of branches of toluene; Combining methylbenzene solution; Anhydrous sodium sulfate drying; Filter; Concentrate, the normal hexane crystallization gets white crystalline powder product 49 grams, yield 34%; Fusing point: 94～96 ℃, specific rotatory power: [α]
D≤-21.5 ° (C1, toluene), optical purity:>=99.0%, content:>=99.0%.
Embodiment 3
With 1-[(4-chloro-phenyl-) phenmethyl] piperazine 287 restrains (1 mole) and chiral mandelic acid's ionic liquid joins in the reaction vessel for 2 moles together; In 60 ℃ of reactions 10 hours; With 200 milliliters of extractions of toluene; It is that 10% sodium hydroxide solution transfers to pH=11-12 that reaction system after the extraction is used mass percentage concentration; Again with three extractions of 200 milliliters of branches of toluene; Combining methylbenzene solution; Anhydrous sodium sulfate drying; Filter; Concentrate, the normal hexane crystallization gets white crystalline powder product 53 grams, yield 37%; Fusing point: 94～96 ℃, specific rotatory power: [α]
D≤-21.5 ° (C1, toluene), optical purity:>=99.0%, content:>=99.0%.
Embodiment 4
With 1-[(4-chloro-phenyl-) phenmethyl] piperazine 287 restrains (1 mole) and chirality lactic acid ion liquid joins in the reaction vessel for 2.5 moles together; In 100 ℃ of reactions 1 hour; With 200 milliliters of extractions of toluene; It is that 10% sodium hydroxide transfers to pH=11-12 that reaction system after the extraction is used mass percentage concentration; Again with three extractions of 200 milliliters of branches of toluene; Combining methylbenzene solution; Anhydrous sodium sulfate drying; Filter; Concentrate, the normal hexane crystallization gets white crystalline powder product 49 grams, yield 34%; Fusing point: 94～96 ℃, specific rotatory power: [α]
D≤-21.5 ° (C1, toluene), optical purity:>=99.0%, content:>=99.0%.
Embodiment 5
With 1-[(4-chloro-phenyl-) phenmethyl] piperazine 287 restrains (1 mole) and chirality lactic acid ion liquid joins in the reaction vessel for 3 moles together; In 80 ℃ of reactions 3 hours; With 200 milliliters of extractions of toluene; It is that 10% sodium hydroxide transfers to pH=11-12 that reaction system after the extraction is used mass percentage concentration; Again with three extractions of 200 milliliters of branches of toluene; Combining methylbenzene solution; Anhydrous sodium sulfate drying; Filter; Concentrate, the normal hexane crystallization gets white crystalline powder product 51.8 grams, yield 36%; Fusing point: 94～96 ℃, specific rotatory power: [α]
D≤-21.5 ° (C1, toluene), optical purity:>=99.0%, content:>=99.0%.
Claims (10)
1. the method for splitting of a levocetirizine chiral intermediate is characterized in that described method for splitting comprises the steps:
1) described levocetirizine chiral intermediate is (R)-1-[(4-chloro-phenyl-) phenmethyl] piperazine, the structural formula of described levocetirizine chiral intermediate and chiral ionic liquid is shown in formula I, formula II:
（Ⅰ） （Ⅱ）
2) with 1-[(4-chloro-phenyl-) phenmethyl of racemization] piperazine and the chiral ionic liquid shown in formula II join in the reaction vessel together; Reacted 1-10 hour down in 10-100 ℃ temperature condition; Reaction finishes the back extracted in toluene; Layering; Toluene layer is used for racemization, and water is for further processing;
3) with step 2) in the water that obtains to use mass percent concentration be that 10% sodium hydroxide solution transfers to pH to 11-12, use extracted in toluene again, obtain as 1 through condensing crystal after the aftertreatment) in the product shown in the formula I.
2. the method for splitting of a kind of levocetirizine chiral intermediate according to claim 1 is characterized in that R is the substituted alkyl of C1-C10 in the described chiral ionic liquid, described negatively charged ion L
-Alcohol acid is a R-lactic acid, any one in R-tartrate or the R-amygdalic acid.
3. the method for splitting of a kind of levocetirizine chiral intermediate according to claim 1 is characterized in that step 2) described in temperature of reaction be 30-60 ℃.
4. the method for splitting of a kind of levocetirizine chiral intermediate according to claim 1 is characterized in that step 2) described in reaction times be 3-6 hour.
5. the method for splitting of a kind of levocetirizine chiral intermediate according to claim 1 is characterized in that step 2) 1-[(4-chloro-phenyl-) phenmethyl of described racemization] molar ratio of piperazine and chiral ionic liquid is 1:2-3.
6. the method for splitting of a kind of levocetirizine chiral intermediate according to claim 1; It is characterized in that the described post-treating method of step 3) is following: the toluene layer after the extracted in toluene is dry earlier; Evaporated under reduced pressure solvent again; Obtain crude product, with the normal hexane crystallization must be shown in formula I product.
7. the method for splitting of a kind of levocetirizine chiral intermediate according to claim 2, it is characterized in that described chiral ionic liquid wherein R be the substituted alkyl of C1-C6, alcohol acid L
-Be the R-amygdalic acid.
8. the method for splitting of a kind of levocetirizine chiral intermediate according to claim 3 is characterized in that step 2) described in temperature of reaction be 40-50 ℃.
9. the method for splitting of a kind of levocetirizine chiral intermediate according to claim 4 is characterized in that step 2) described in reaction times be 4-5 hour.
10. the method for splitting of a kind of levocetirizine chiral intermediate according to claim 5 is characterized in that step 2) 1-[(4-chloro-phenyl-) phenmethyl of described racemization] molar ratio of piperazine and chiral ionic liquid is 1:2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110235025.6A CN102351810B (en) | 2011-08-17 | 2011-08-17 | Resolution method of levocetirizine chiral intermediates |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103387534A (en) * | 2012-05-09 | 2013-11-13 | 北大方正集团有限公司 | Method for separating tropicamide raceme |
| CN103664998A (en) * | 2013-10-28 | 2014-03-26 | 中建安装工程有限公司 | Split reagent and method for ofloxacin racemic mixture |
| CN103709176A (en) * | 2013-10-28 | 2014-04-09 | 中建安装工程有限公司 | Reagents and method for separation of ofloxacin racemic mixture by utilization of ionic liquid and L-dibenzoyltartaric acid together |
| CN104788469A (en) * | 2015-04-14 | 2015-07-22 | 临海市利民化工有限公司 | Preparation method of clopidogrel bisulfate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101928223A (en) * | 2009-06-26 | 2010-12-29 | 华东理工大学 | Resolution method of (R)-(-)-4-chloro benzhydrylamine |
-
2011
- 2011-08-17 CN CN201110235025.6A patent/CN102351810B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101928223A (en) * | 2009-06-26 | 2010-12-29 | 华东理工大学 | Resolution method of (R)-(-)-4-chloro benzhydrylamine |
Non-Patent Citations (1)
| Title |
|---|
| 孙洪海等: "手性离子液体的合成", 《化学进展》, vol. 20, no. 5, 31 May 2008 (2008-05-31), pages 698 - 712 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103387534A (en) * | 2012-05-09 | 2013-11-13 | 北大方正集团有限公司 | Method for separating tropicamide raceme |
| CN103387534B (en) * | 2012-05-09 | 2015-02-18 | 北大方正集团有限公司 | Method for separating tropicamide raceme |
| CN103664998A (en) * | 2013-10-28 | 2014-03-26 | 中建安装工程有限公司 | Split reagent and method for ofloxacin racemic mixture |
| CN103709176A (en) * | 2013-10-28 | 2014-04-09 | 中建安装工程有限公司 | Reagents and method for separation of ofloxacin racemic mixture by utilization of ionic liquid and L-dibenzoyltartaric acid together |
| CN103709176B (en) * | 2013-10-28 | 2015-10-07 | 中建安装工程有限公司 | Ionic liquid and L-dibenzoyl tartaric acid is utilized jointly to split reagent and the method for separation of ofloxacin racemic mixture |
| CN103664998B (en) * | 2013-10-28 | 2016-03-30 | 中建安装工程有限公司 | The resolution reagent of separation of ofloxacin racemic mixture and method |
| CN104788469A (en) * | 2015-04-14 | 2015-07-22 | 临海市利民化工有限公司 | Preparation method of clopidogrel bisulfate |
| CN104788469B (en) * | 2015-04-14 | 2017-03-01 | 临海市利民化工有限公司 | A kind of preparation method of Clopidogrel Bisulfate |
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Denomination of invention: A Resolution Method for Chiral Intermediates of Levocetirizine Effective date of registration: 20231226 Granted publication date: 20150715 Pledgee: Zhejiang Changshan Rural Commercial Bank Co.,Ltd. Pledgor: ZHEJIANG EVER JOINT NEW MATERIAL TECHNOLOGY CO.,LTD. Registration number: Y2023330003114 |