CN104151249B - Medetomidine industrialization method for splitting - Google Patents
Medetomidine industrialization method for splitting Download PDFInfo
- Publication number
- CN104151249B CN104151249B CN201410332901.0A CN201410332901A CN104151249B CN 104151249 B CN104151249 B CN 104151249B CN 201410332901 A CN201410332901 A CN 201410332901A CN 104151249 B CN104151249 B CN 104151249B
- Authority
- CN
- China
- Prior art keywords
- ethyl
- imidazoles
- medetomidine
- xylyl
- splitting
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- 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.)
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 229960002140 medetomidine Drugs 0.000 title claims abstract description 11
- HRLIOXLXPOHXTA-UHFFFAOYSA-N medetomidine Chemical compound C=1C=CC(C)=C(C)C=1C(C)C1=CN=C[N]1 HRLIOXLXPOHXTA-UHFFFAOYSA-N 0.000 title claims abstract 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 229950005953 camsilate Drugs 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 3
- 238000007796 conventional method Methods 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- CDULGHZNHURECF-UHFFFAOYSA-N 2,3-dimethylaniline 2,4-dimethylaniline 2,5-dimethylaniline 2,6-dimethylaniline 3,4-dimethylaniline 3,5-dimethylaniline Chemical group CC1=CC=C(N)C(C)=C1.CC1=CC=C(C)C(N)=C1.CC1=CC(C)=CC(N)=C1.CC1=CC=C(N)C=C1C.CC1=CC=CC(N)=C1C.CC1=CC=CC(C)=C1N CDULGHZNHURECF-UHFFFAOYSA-N 0.000 claims 3
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 230000003287 optical effect Effects 0.000 abstract description 8
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 abstract description 4
- 238000005194 fractionation Methods 0.000 abstract description 2
- 239000012069 chiral reagent Substances 0.000 abstract 1
- CUHVIMMYOGQXCV-UHFFFAOYSA-N medetomidine Chemical compound C=1C=CC(C)=C(C)C=1C(C)C1=CNC=N1 CUHVIMMYOGQXCV-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- VPNGEIHDPSLNMU-MERQFXBCSA-N dexmedetomidine hydrochloride Chemical compound Cl.C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CNC=N1 VPNGEIHDPSLNMU-MERQFXBCSA-N 0.000 description 7
- 229960002746 dexmedetomidine hydrochloride Drugs 0.000 description 7
- 238000003756 stirring Methods 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229960000935 dehydrated alcohol Drugs 0.000 description 4
- 229960004253 dexmedetomidine Drugs 0.000 description 4
- HRLIOXLXPOHXTA-NSHDSACASA-N dexmedetomidine Chemical compound C1([C@@H](C)C=2C(=C(C)C=CC=2)C)=CN=C[N]1 HRLIOXLXPOHXTA-NSHDSACASA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 235000011002 L(+)-tartaric acid Nutrition 0.000 description 2
- 239000001358 L(+)-tartaric acid Substances 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 1
- -1 2,3- xylyl Chemical group 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 210000004247 hand Anatomy 0.000 description 1
- AUONNNVJUCSETH-UHFFFAOYSA-N icosanoyl icosanoate Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCCCCCCCCCC AUONNNVJUCSETH-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 230000002618 waking effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
Abstract
The invention discloses a kind of medetomidine industrialization method for splitting.The method, using L () camphorsulfonic acid as chiral reagent, is the alcohol of Cl～C5 as chiral auxiliary.Method of the present invention resolution yield up to more than 40%, the optical purity of fractionation reaches more than 99.5%, has simple industrial operation, can be used for industrialization and commercially produces.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, relate in particular to the industrialization method for splitting of medetomidine.
Background technology
Dexmedetomidine hydrochloride injection at home and abroad all lists at present, and it is as a kind of short-acting, potent, high selectivity
α2- adrenoceptor agonists, have calmness, analgesia, anxiety and to breathing unrestraint the features such as；High selectivity is allowed to
Rarely has the untoward reaction that clonidine has.Keep while calm waking up ability.This medicine does not induce the breathing of clinical meaning
Suppression, makes tube drawing safer, and may make patient's tube drawing and remove machine as early as possible；Clinically it is widely used for all kinds of handss simultaneously
Tranquilizer in the preoperative and art of art, therefore, dexmedetomidine hydrochloride injection has become the calm line options of clinicist.
The essential information of dexmedetomidine hydrochloride is as follows：
Common name：Dexmedetomidine hydrochloride
English name：Dexmedetomidine hydrochloride
Chemical name：(+) -4- (S)-[1- (2,3- 3,5-dimethylphenyl) ethyl] -1H- imidazole hydrochloride
The Chinese phonetic alphabet：Yansuan Youmeituomiding
Chemical constitution：
Molecular formula：C13H16N2·HCl
Molecular weight：236.74
Character：White or off-white powder；Odorless, has hygroscopicity.
Dissolubility：This product easily dissolves in water, soluble in ethanol or chloroform, almost insoluble in ethanol.
WO 20130225832 and WO 2013069025 all using L- (+)-tartaric acid passes through double resolution and repeatedly again tying
Crystalline substance obtains the right Mei Tuomei pyridine of the extremely low hydrochloric acid of yield.
CN1022323C discloses and uses D- from racemic modification（-）The dextrorotation pair of-tartaric acid separation medetomidine derivant
The method reflecting body, W09715302 with similar method, by resolving agent L- (+)-tartaric acid D-（-)-tartaric acid replacement, pass through
Repeat to crystallize the single levo-enantiomer less than the 0.30% of two kinds of enantiomer total contents for the content having obtained dextrorotatory antipode.This
Class method complex operation, and the requirement of difficult to reach optical purity in many cases.
CN 101671305A discloses and uses D-（+）- dibenzoyl tartaric acid, L- (-)-dibenzoyl winestone
Acid, S- (+)-phosphoric acid-hydrogen -1,1 '-connection -2,2 '-naphthalene ester, R- (-)-phosphoric acid-hydrogen -1,1 '-connection -2, salt is prepared in the ester fractionation of 2 '-naphthalene
The right Mei Tuomei pyridine of acid and the method for hydrochloric acid left Mei Tuomei pyridine, prepare in the method, and yield appoints so very low and product optical voidness
Degree is low.
Other have no the report to the method separating medetomidine enantiomer for the domestic and foreign literature.
Content of the invention
In order to solve medetomidine in prior art [i.e. (scholar) 4- [1- (2,3- xylyl)-ethyl] -1H- imidazoles]
The not high problem of resolution yield, the invention provides a kind of method for splitting of new medetomidine, its optical purity up to
More than 99.5%, and yield is up to more than 40%.
The technical solution used in the present invention is as follows：
A kind of method for splitting of medetomidine, is with structure such as formula（I）Shown (scholar) 4- [1- (2,3- xylyl)-
Ethyl] -1H- imidazoles and L- (-) after camphorsulfonic acid 0～100 DEG C of reaction of what in resolution solvent crystallization separate out structure such as formula (II)
Shown (+) L- of -4- (S)-[1- (2,3- xylyl)-ethyl] -1H- imidazoles (-) camsilate, (+) -4-
(S)-[1- (2,3- xylyl)-ethyl] -1H- imidazoles L- (-) camsilate post-treated obtain (+) -4-
(S)-[1- (2,3- xylyl)-ethyl] -1H- imidazoles, (+) -4- (S)-[1- (2,3- xylyl)-ethyl] -
1H- imidazoles formulates hydrochloric acid right Mei Tuomei pyridine with conventional method hydrochloric acid salt again, resolution solvent used in the present invention be Cl～
The alcohol of C5.(scholar) used in the present invention 4- [1- (2,3- xylyl)-ethyl] -1H- imidazoles and L- (-) camphorsulfonic acid
The mol ratio that feeds intake is 1:0.4～1.0, preferably 1:0.5.
The alcohol of C1～C5 of the present invention is selected from one of following：Methanol, ethanol, isopropanol, propanol, n-butyl alcohol, preferably
Ethanol.
Preferably 60～80 DEG C of resolution reaction temperature of the present invention.
Scholar of the present invention) 4- [1- (2,3- xylyl)-ethyl] -1H- imidazoles and resolution solvent w/v
For 1：15～20.
Advantages of the present invention：
The method for splitting that the present invention provides has efficiency high, and its resolution yield has reached more than 40%, splits material simultaneously
Optical purity, up to more than 99.5%, has simple industrial operation, can be used for industrialization and commercially produces.
Specific embodiment
The following examples can conduct further description to the present invention, however, these embodiments should not be used as to this
The restriction of invention scope.
Embodiment 1：（S）- medetomidine L- (-) preparation of camsilate
It is separately added into 400g in 20L reactor（2.0mol）Medetomidine, dehydrated alcohol 10L, L- (-) camphorsulfonic acid
233g（1.0mol）, stirring intensification, 75 ± 5 DEG C of dissolving backflow 20min, temperature is down to 5 ± 2 DEG C of crystallize 18h naturally.Sucking filtration, 300
Dehydrated alcohol is washed and starched, and is filtered dry, and 50 DEG C of vacuum decompressions of filter cake are dried 5h and obtain white solid（S）- medetomidine L- (-) camsilate
415g, yield 46%, optical purity is 99.6%.
Embodiment 2：（S）- medetomidine L- (-) preparation of camsilate
It is separately added into 400g in 20L reactor（2.0mol）Medetomidine, dehydrated alcohol 12L, L- (-) camphorsulfonic acid
345g（1.5mol）, stirring intensification, 75 ± 5 DEG C of dissolving backflow 20min, temperature is down to 5 ± 2 DEG C of crystallize 18h naturally.Sucking filtration, 350
Dehydrated alcohol is washed and starched, and is filtered dry, and 50 DEG C of vacuum decompressions of filter cake are dried 5h and obtain white solid（S）- medetomidine L- (-) camsilate
419g, yield 46.7%, optical purity is 99.8%.
Embodiment 3：The preparation of dexmedetomidine hydrochloride
Put into dichloromethane 3500ml respectively in 10L reaction bulb, water 2000ml, embodiment 1 compound 200g stirring is molten
Solution, adjusts pH value 9 ± 1, stratification after pH stable with strong aqua ammonia, organic faciess 700ml × 2 are washed, anhydrous sodium sulfate stirs
To clarifying, 3h, sucking filtration are dried, dichloromethane 500ml rinses filter cake, merge mother solution, 40 ± 5 DEG C of evaporated under reduced pressure, obtain white solid.
Gained white solid is dissolved in 1500ml dichloromethane, instills 10N ethanol solution hydrochloride 87ml, stirring reaction 20min is then fast
Speed instills absolute ether 6000ml, stirring and crystallizing 5h.Sucking filtration, absolute ether washes and starches filter cake, and filter cake, in 60 DEG C of drying under reduced pressure 6h, obtains
White solid dexmedetomidine hydrochloride 102g.Yield 93%, optical purity is 100%.
Claims (1)
1. a kind of method for splitting of medetomidine, described method is (scholar) 4- [1- (2,3- bis- with structure as shown in formula (I)
Tolyl)-ethyl] -1H- imidazoles and L- (-) after camphorsulfonic acid reacts in resolution solvent crystallization separate out structure such as formula (II) institute
Show (+) L- of -4- (S)-[1- (2,3- xylyl)-ethyl] -1H- imidazoles (-) camsilate, (+) -4- (S)-[1-
(2,3 xylidine base)-ethyl] -1H- imidazoles L- (-) camsilate post-treated obtain (+) -4- (S)-[1- (2,3-
Xylyl)-ethyl] -1H- imidazoles, (+) -4- (S)-[1- (2,3- xylyl)-ethyl] -1H- imidazoles uses conventional method again
Hydrochloric acid salt and formulate hydrochloric acid right Mei Tuomei pyridine it is characterised in that described resolution solvent is ethanol, described (scholar) 4- [1-
(2,3 xylidine base)-ethyl] -1H- imidazoles and L- (-) mol ratio that feeds intake of camphorsulfonic acid is 1:0.4～1.0；
Described resolution reaction temperature is 60～80 DEG C；
The w/v of described (scholar) 4- [1- (2,3 xylidine base)-ethyl] -1H- imidazoles and resolution solvent is 1:15～
25.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410332901.0A CN104151249B (en) | 2014-07-14 | 2014-07-14 | Medetomidine industrialization method for splitting |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410332901.0A CN104151249B (en) | 2014-07-14 | 2014-07-14 | Medetomidine industrialization method for splitting |
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| CN104151249A CN104151249A (en) | 2014-11-19 |
| CN104151249B true CN104151249B (en) | 2017-03-08 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175339B (en) * | 2015-10-09 | 2018-01-16 | 辰欣药业股份有限公司 | A kind of method for preparing dexmedetomidine hydrochloride |
| CN105175340A (en) * | 2015-10-26 | 2015-12-23 | 海南通用康力制药有限公司 | Method for preparing high-purity dexmedetomidine hydrochloride crystal from high-purity intermediate crystal |
| CN106632053B (en) * | 2016-12-20 | 2019-01-08 | 徐州医科大学 | A kind of method for splitting of dexmedetomidine hydrochloride intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101671305A (en) * | 2009-09-29 | 2010-03-17 | 北京华禧联合科技发展有限公司 | Method for resolution of levorotatory enantiomer and dexiotropic enantiomer of medetomidine |
| WO2013069025A1 (en) * | 2011-11-11 | 2013-05-16 | Neon Laboratories Ltd. | "process for the preparation of dexmedetomidine" |
| CN103694175A (en) * | 2013-12-18 | 2014-04-02 | 北京华禧联合科技发展有限公司 | New method for preparing dexmedetomidine hydrochloride |
-
2014
- 2014-07-14 CN CN201410332901.0A patent/CN104151249B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101671305A (en) * | 2009-09-29 | 2010-03-17 | 北京华禧联合科技发展有限公司 | Method for resolution of levorotatory enantiomer and dexiotropic enantiomer of medetomidine |
| WO2013069025A1 (en) * | 2011-11-11 | 2013-05-16 | Neon Laboratories Ltd. | "process for the preparation of dexmedetomidine" |
| CN103694175A (en) * | 2013-12-18 | 2014-04-02 | 北京华禧联合科技发展有限公司 | New method for preparing dexmedetomidine hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| 盐酸右美托咪定合成路线图解;王鸿钢;《中国医药工业杂志》;20081231;第39卷(第6期);全文 * |
| 盐酸右美托咪定的合成;王玉平;《广东药学院学报》;20120425;第28卷(第2期);全文 * |
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| CN104151249A (en) | 2014-11-19 |
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