CN102627595A - Method for preparation of glycopyrronium bromide - Google Patents
Method for preparation of glycopyrronium bromide Download PDFInfo
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- CN102627595A CN102627595A CN201210069208XA CN201210069208A CN102627595A CN 102627595 A CN102627595 A CN 102627595A CN 201210069208X A CN201210069208X A CN 201210069208XA CN 201210069208 A CN201210069208 A CN 201210069208A CN 102627595 A CN102627595 A CN 102627595A
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- 229960002462 glycopyrronium bromide Drugs 0.000 title claims abstract description 45
- VPNYRYCIDCJBOM-UHFFFAOYSA-M Glycopyrronium bromide Chemical compound [Br-].C1[N+](C)(C)CCC1OC(=O)C(O)(C=1C=CC=CC=1)C1CCCC1 VPNYRYCIDCJBOM-UHFFFAOYSA-M 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- 239000002994 raw material Substances 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- FLVFPAIGVBQGET-UHFFFAOYSA-N 1-methylpyrrolidin-3-ol Chemical compound CN1CCC(O)C1 FLVFPAIGVBQGET-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 235000007244 Zea mays Nutrition 0.000 claims description 5
- 240000008042 Zea mays Species 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000002844 melting Methods 0.000 abstract description 2
- 230000008018 melting Effects 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract 1
- 238000000746 purification Methods 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 6
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- -1 methyl-magnesium-bromide Grignard reagent Chemical class 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000004176 ammonification Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 229940106905 robinul Drugs 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GGRLKHMFMUXIOG-UHFFFAOYSA-M 2-acetyloxyethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].CC(=O)OCC[N+](C)(C)C GGRLKHMFMUXIOG-UHFFFAOYSA-M 0.000 description 1
- KOAOCPHCXHHYIY-UHFFFAOYSA-N 6-chloro-2,4-dimethoxy-1h-triazine Chemical compound CON1NC(Cl)=CC(OC)=N1 KOAOCPHCXHHYIY-UHFFFAOYSA-N 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- HARKFXYBBMWHFR-UHFFFAOYSA-N CCC(C)CCC(CC)OC(C(C1CCCC1)(c1ccccc1C)OC)=O Chemical compound CCC(C)CCC(CC)OC(C(C1CCCC1)(c1ccccc1C)OC)=O HARKFXYBBMWHFR-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010062530 Increased bronchial secretion Diseases 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 241001062472 Stokellia anisodon Species 0.000 description 1
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000001022 anti-muscarinic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000019636 bitter flavor Nutrition 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 239000000544 cholinesterase inhibitor Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 210000005037 parasympathetic nerve Anatomy 0.000 description 1
- 230000008855 peristalsis Effects 0.000 description 1
- 210000003800 pharynx Anatomy 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to the field of chemical synthesis, relates to a method for preparation of glycopyrronium bromide, and especially relates to enriched high-purity (3R, 2'S,) and (3S, 2'R,) glycopyrronium bromide and a preparation method of a novel intermediate involved in the synthesis method of glycopyrronium bromide. The method provided by the invention overcomes the defect that the prior art has a low yield and can produce large pollution, can realize preparation of glycopyrronium bromide shown in the formula I, has a high yield, produces low environmental pollution and is convenient for purification. Glycopyrronium bromide obtained by the method has a melting point of 195 to 198 DEG C.
Description
One, technical field
The invention belongs to the field of chemical synthesis, more specifically to the preparation method of Glycopyrronium Bromide.
Two, background technology
Glycopyrronium Bromide is by U.S. SHIONOGI INC research and development, and in nineteen eighty-two first at the U.S.'s its Glycopyrronium Bromide sheet of listing; The same year is by U.S. BAXTER HEALTHCARE CORPANESTHESIAAND CRITICAL CAR research and development and at the U.S.'s its Glycopyrronium Bromide injection liquid of listing.In October, 2010, the domestic production of " the Glycopyrronium Bromide raw material and the tablet " of approval Hunan Dongting Pharmaceutical Co., Ltd. of National Drug Administration, authentication code is: the accurate word H43020556 of traditional Chinese medicines.These article are since appearing on the market, and the preanesthetic medication patient is countless before treating gastrointestinal illness and being used for art.In order to satisfy the demand of clinical patients, alleviate patient's economical load, standard pharmaceutical research simultaneously improves the drug quality of these article, and I have developed Glycopyrronium Bromide bulk drug and injection liquid voluntarily.
These article are quaternary ammonium salts antimuscarinic drugs; Can block the activity of the vagusstoff of parasympathetic nerve tip release; Relaxing smooth muscle; Simultaneously can reduce gastric acid secretion, reduce the secretion of pharynx, trachea and bronchus mucous membrane, and can antagonism bronchorrhea too much, bronchospasm, bradyrhythmia and the intestinal peristalsis muscarinism symptom that causes by anticholinesterase such as too fast.
These article are white crystalline powder; Nothing is smelt, mildly bitter flavor; These article are prone to dissolve in water, methyl alcohol or ethanol; Almost insoluble in trichloromethane or ether.Chinese Pharmacopoeia stipulates that its fusing point is 193.0～198.0 ℃, and its structural formula is following:
Glycopyrronium Bromide
Document US 2956062 and Franko et al, J Med Pharm Chem, the compound method of 2,523 reports is:
This method is a starting raw material with α-cyclopentyl methyl mandelate; Do under the solvent to do alkali and 1-methyl-3-pyrrolidinol through transesterification reaction at normal heptane with sodium Metal 99.5; After making product, distillation in ethyl acetate solvent, carries out the season ammonification with monobromethane; Make the Glycopyrronium Bromide bullion,, make the highly finished product Glycopyrronium Bromide through butanone and ETHYLE ACETATE mixed solvent recrystallization.This method is used sodium Metal 99.5 and low molecular hydrocarbon, and is inflammable and explosive, can't guarantee safety in production, and productive rate is extremely low simultaneously, can't obtain clinical pharmaceutical grade Glycopyrronium Bromide.
Document US 2009/0005577 disclosed synthetic side is:
This method is a starting raw material with α-cyclopentyl racemic melic acid, makes α-cyclopentyl methyl mandelate through the methyl-sulfate esterification, thereafter preparation method and U.S. Pat 2956062 and Franko et al; J Med Pharm Chem, 2,523 (1960) is basic identical; Only recrystallization solvent changes ETHYLE ACETATE into and low mass molecule alcohol is made mixed solvent, high purity made and contained (2R, 3S) and (2S; 3R) raceme Glycopyrronium Bromide, this diastereomer are the Glycopyrronium Bromide of clinical requirement, though this method has made the diastereomeric compound of the clinical needs of high purity; But used great toxicity methylating reagent methyl-sulfate; Simultaneously also used sodium Metal 99.5 and low molecular hydrocarbon, inflammable and explosive, can't guarantee safety in production equally.
Document CN 101133021 disclosed synthetic sides do
This method is disclosed to be the crystallization and the purifying of Glycopyrronium Bromide; Its bullion synthesis route is basically according to the method for US 2956062; But season aminating reaction use acetone is made solvent; After obtaining each enantiomeric mixture of Glycopyrronium Bromide, make the clinical pharmaceutical grade Glycopyrronium Bromide of based on very high purity through methyl alcohol and three re-crystallization step of butanone.Though this process method reaches the pharmaceutical grade standard, the production shortcoming is the same basically, repeats no more.
The document medicine industry, 3,1974, p 8～10 and organic drug synthesize handbook, and the compound method of p 810～812 reports is:
Changde Municipal Dongting Pharmaceutical Factory is published in medicine industry; 3; 1974; The document of p 8～10 is inscribeed one's name---and " organic drug synthesizes handbook to the books that Peptic Ulcers new drug-robinul trial-produces successfully and Shanghai Institute of Pharmaceutical Industry writes, and p 810～812, is starting raw material with basic raw material vinylbenzene; Do acid catalyst esterification, cyclopentadiene and the replacement of methyl-magnesium-bromide Grignard reagent, catalyst activity nickel and hydrogen reducing, 1-methyl-3-pyrrolidinol and sodium Metal 99.5 transesterify through potassium permanganate oxidation, methyl alcohol and sulfuric acid, become the season ammonification to make the bullion Glycopyrronium Bromide at last.This technology is early stage production technique, exists reactions step many, and yield is extremely low, finished product is off quality, clinical shortcoming that can not be medicinal.
The document medicine industry, 3,1979, the compound method of p 10～12 reports is:
Dongting Lake pharmaceutical factory is published in medicine industry; 3,1979, the document autograph of p 10～12---robinul's grignard reaction, ester exchange process improve; With the phenyl glyoxilic acid methyl ester is starting raw material; Reach with the 1-methyl-3-pyrrolidinol ester-interchange method makes the key intermediate of Glycopyrronium Bromide through grignard reaction, catalytic hydrogenation with cyclopentadiene and methyl-magnesium-bromide,, do not carry out technological innovation though this method has been familiar with the deficiency of above production technique; Its shortcoming clearly can't guarantee to keep the safety in production and obtain qualified clinical pharmaceutical grade Glycopyrronium Bromide.
More than the synthetic Glycopyrronium Bromides of several synthetic routes all exist productive rate extremely low, the shortcoming that operation easier is big.High to equipment and environmental requirement, be not suitable for suitability for industrialized production.
Based on the research in the relative merits of above synthetic route and the practice with grope, according to market starting raw material cheap and easy to get, the Glycopyrronium Bromide production technique that I control oneself and have confirmed accords with production and clinical medicinal standard.
Three, summary of the invention
The objective of the invention is to remedy the weak point that exists in the prior art, a kind of method of preparing Glycopyrronium Bromide different with already known processes is provided, the industrialized producing technology that this explained hereafter is simple, product yield increases substantially.With low cost, advantages such as pollution is little, process stabilizing that technology of the present invention has.Product enrichment high purity (3R, 2 ' S) and (3S, 2 ' R) Glycopyrronium Bromide, the Glycopyrronium Bromide fusing point of this method preparation is 195 ℃～198 ℃, meets clinical medicinal standard fully.
The new preparation technology of the present invention is following:
Reactions step is:
A) be starting raw material and 4-chloro-2 with α-cyclopentyl racemic melic acid, the 6-dimethoxy-triazine makes formula (II) compound solution in organic solvent:
B) in the solution of formula (II) compound, directly add the organic solution of 1-methyl-3-pyrrolidinol, formula (III) compound solution:
C) in the solution of formula (III) compound, directly splash into monobromethane and promptly get Glycopyrronium Bromide.
The invention provides the compound method of a brand-new synthetic Glycopyrronium Bromide thing, its Chinese style (II) compound is new synthetic intermediate.
The organic solvent that step a) of the present invention is used is selected from toluene, Virahol, n-propyl alcohol, butanone, preferred toluene.Temperature is a room temperature.
The organic solvent of step b) dissolving 1-methyl of the present invention-3-pyrrolidinol is selected from Virahol.
Through enforcement of the present invention, the Glycopyrronium Bromide for preparing, enrichment high purity (3R, 2 ' S) and (3S, 2 ' R) Glycopyrronium Bromide, and the Glycopyrronium Bromide melting range is 195 ℃～198 ℃, meets clinical pharmaceutical injection rank fully.
Advantage of the present invention:
Raw material of the present invention is easy to get, cheap, synthetic operation is simple, reaction conditions is gentle, be easy to control, good reaction selectivity, yield is very high, environmental pollution is minimum, is easy to suitability for industrialized production.
Four, description of drawings
Fig. 1 is the U.S. BAXTER HEALTHCARE CORPANESTHESIAAND CRITICAL CAR Glycopyrronium Bromide injection liquid HPLC of a company color atlas
Fig. 2 is oneself synthetic Glycopyrronium Bromide raw material HPLC color atlas
Fig. 3 is the Glycopyrronium Bromide injection liquid HPLC color atlas that oneself is developed
Five, embodiment
Following embodiment can further describe the present invention, yet these embodiment should be as limitation of the scope of the invention.
Embodiment:
A) in 10L dry reaction still, add α-cyclopentyl racemic melic acid 440g, toluene 6L, under the stirring at room, add 4-chloro-2,6-dimethoxy-triazine 360g stirs 20min, promptly gets the active intermediate solution of formula (II)
B) in above-mentioned solution, add the 300ml aqueous isopropanol of 200g1-methyl-3-pyrrolidinol, at 1h internal heating to 60 ℃, kept stirring reaction 5 hours
C) the above-mentioned solution of cooling splashes into the 210g monobromethane to-20 ℃, insulated and stirred 2h, after be warming up to 60 ℃ and keep stirring 20min, be cooled to room temperature, leave standstill 5h, filter, solid is used a small amount of washed with isopropyl alcohol, 70～80 ℃ of vacuum-dryings get Glycopyrronium Bromide 361g.Yield counts 89.5%, fusing point with α-cyclopentyl racemic melic acid: 195 ℃～198 ℃.
1H-NMR(600MHz，CDCl
3/TMS，ppm)：
δ1.07～1.09(m，1H)；δ1.28～1.31(m，1H)；δ1.37～1.43(m，1H)；δ1.45～1.53(m，1H)；δ1.57～1.63(m，1H)；δ1.69～1.72(m，1H)；δ1.82～1.84(m，1H)；δ2.7～3.0(m，1H，H-C10)；δ3.13～3.15(m，2H，H-C7)；δ6.82(1H，H-C5)；δ7.05(1H，H-C4)；δ7.35(1H，H-C18)；δ7.53(2H，H-C17，H-C19)
MS：m/z(M
+)396.12(100％)
Claims (5)
1. method for preparing the Glycopyrronium Bromide of formula (I) structure is characterized in that this method may further comprise the steps:
A) be starting raw material and 4-chloro-2 with α-cyclopentyl racemic melic acid, the 6-dimethoxy-triazine makes formula (II) compound solution in organic solvent:
B) in the solution of formula (II) compound, directly add the organic solution of 1-methyl-3-pyrrolidinol, formula (III) compound solution:
C) in the solution of formula (III) compound, directly splash into monobromethane and promptly get the Glycopyrronium Bromide bullion.
2. a kind of method for preparing Glycopyrronium Bromide according to claim 1 is characterized in that: formula (II) compound is new synthetic intermediate.
3. a kind of method for preparing Glycopyrronium Bromide according to claim 1, wherein the organic solvent of step a) use is selected from toluene, Virahol, n-propyl alcohol, butanone.
4. a kind of method for preparing Glycopyrronium Bromide according to claim 1, wherein the step a) temperature of reaction is a room temperature.
5. a kind of method for preparing Glycopyrronium Bromide according to claim 1, wherein the organic solvent of step b) dissolving 1-methyl-3-pyrrolidinol is selected from Virahol.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103819384A (en) * | 2013-12-05 | 2014-05-28 | 广东嘉博制药有限公司 | Preparation method of glycopyrronium bromide |
| CN107345945A (en) * | 2016-05-05 | 2017-11-14 | 辽宁药联制药有限公司 | A kind of efficient liquid-phase chromatography method for splitting glycopyrronium bromide enantiomer and determination of foreign matter |
| CN113861030A (en) * | 2020-06-30 | 2021-12-31 | 天津药业研究院股份有限公司 | Glycopyrronium bromide intermediate and preparation method and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103819384A (en) * | 2013-12-05 | 2014-05-28 | 广东嘉博制药有限公司 | Preparation method of glycopyrronium bromide |
| CN107345945A (en) * | 2016-05-05 | 2017-11-14 | 辽宁药联制药有限公司 | A kind of efficient liquid-phase chromatography method for splitting glycopyrronium bromide enantiomer and determination of foreign matter |
| CN107345945B (en) * | 2016-05-05 | 2019-12-17 | 辽宁药联制药有限公司 | High performance liquid chromatography method for resolving glycopyrronium bromide enantiomer and checking impurities |
| CN113861030A (en) * | 2020-06-30 | 2021-12-31 | 天津药业研究院股份有限公司 | Glycopyrronium bromide intermediate and preparation method and application thereof |
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