CN103159659A - Preparation method of muscarinic receptor antagonist glycopyrronium bromide - Google Patents
Preparation method of muscarinic receptor antagonist glycopyrronium bromide Download PDFInfo
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- CN103159659A CN103159659A CN2011104260381A CN201110426038A CN103159659A CN 103159659 A CN103159659 A CN 103159659A CN 2011104260381 A CN2011104260381 A CN 2011104260381A CN 201110426038 A CN201110426038 A CN 201110426038A CN 103159659 A CN103159659 A CN 103159659A
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Abstract
The invention belongs to the technical field of medicine and discloses a preparation method of muscarinic receptor antagonist glycopyrronium bromide. The preparation method of the muscarinic receptor antagonist glycopyrronium bromide is characterized in that Alpha-cyclopentyl mandelic acid methyl ester is obtained by aceptophenone ketonic acid Grignard reaction and esterification reaction, and then glycopyrronium bromide is obtained by N-methyl pyrrolidine-3-alcohol ester exchange and quaterisation.
Description
Technical field:
The invention belongs to medical technical field, relate to a kind of preparation method of Glycopyrronium Bromide.
Background technology:
Glycopyrronium Bromide (Glycopyrrolate,
1), chemistry 3-(α-cyclopentyl hydroxybenzene acetoxyl group)-1 by name, 1-dimethyl pyrrolidine bromine ammonium salt, by the exploitation of Japanese Shionogi company, nineteen eighty-two, the preparation of listing was tablet at home at present in U.S.'s approval listing, the trade(brand)name robinul.This product is M-ChR (m receptor) antagonist, and is clinical in diseases such as gastric and duodenal ulcer, chronic gastritis, gastrorrheas.
US Patent No. 2956062 report, Glycopyrronium Bromide can α-cyclopentyl methyl mandelate be raw material, under strong alkaline condition with
N-methylpyrrolidin-3-alcohol carries out transesterification reaction, then makes with monobromethane generation quaterisation.The preparation of α-cyclopentyl methyl mandelate mainly contains three kinds of methods: (1) contemporary structure medicament complete or collected works, 1993, report phenyl glyoxilic acid methyl ester and cyclopentadienyl magnesium bromide generation grignard reaction in 1151 literary compositions, then make α-cyclopentyl methyl mandelate through catalytic hydrogenation, but cyclopentadiene is unstable, often exist with the dimer state, the need Pintsch process participates in reaction after making monomer; (2) US Patent No. 3381017 report phenyl glyoxilic acid methyl esters and cyclopentyl bromination magnesium directly make α-cyclopentyl methyl mandelate through grignard reaction; (3) article Journal of pharmacy and pharmacology, 2005, the 1427-1435 report with cyclopentyl bromination magnesium generation grignard reaction, then becomes ester to make α-cyclopentyl methyl mandelate take benzoylformic acid as raw material under Catalyzed by p-Toluenesulfonic Acid with methyl alcohol.this research is at first to method one, method two is studied, result shows, when phenyl glyoxilic acid methyl ester and Grignard reagent react, when the ketone carbonyl is by nucleophilic attack, grignard reaction also can occur in ester carbonyl group, therefore obtain the by product of target intermediate α-cyclopentyl methyl mandelate and two grignards, both polarity is close, separation difficulty, this research is attempted passing through material proportion, temperature of reaction, the generation of two grignard by products is avoided in the adjustment of order of addition(of ingredients), but all not successes, infer thus, the active no significant difference of ketone carbonyl and ester carbonyl group generation grignard reaction in the structure of phenyl glyoxilic acid methyl ester.
After method three was launched research, experimental result showed, although in the benzoylformic acid structure, the existence of carboxyl can consume the Grignard reagent of a mole, has effectively avoided the generation of two format side reactions, and reaction has good selectivity; At intermediate α-cyclopentyl amygdalic acid
NIn the preparation of-methylpyrrolidin-3-ester, adopt heptane as solvent in document, sodium Metal 99.5 is as catalyzer, and operates according to this literature method, and product yield is only 32%.
The preparation method of existing Glycopyrronium Bromide all exists deficiency, so its preparation method awaits further research.
Summary of the invention:
The technical problem that the present invention solves is to provide a kind of preparation method of Glycopyrronium Bromide.
The present invention prepares by the following method:
The benzoylformic acid of US29560628 makes α-cyclopentyl methyl mandelate through grignard reaction, esterification, then with
N-methylpyrrolidin-3-alcohol makes Glycopyrronium Bromide through transesterify, quaterisation.Reaction formula is as follows:
Benzoylformic acid
2: bromocyclopentane
3: magnesiumFor preparing α-cyclopentyl amygdalic acid 5 under 1:1:1 ~ 1:5:1 condition, then make target intermediate α-cyclopentyl methyl mandelate through esterification
6
As solvent, react under reflux conditions by sodium hydride catalysis with normal hexane for intermediate 6, for the forward that promotes reversible reaction moves, constantly steams the methyl alcohol of generation in reaction simultaneously.
Prepared Glycopyrronium Bromide can be used butanone, acetone, acetonitrile refining; α-cyclopentyl amygdalic acid 5 is used methylene dichloride, ethylene dichloride, and butanone is refining.
Embodiment
α-cyclopentyl amygdalic acid (5)
Add magnesium chips (1.5g, 62mmol), anhydrous diethyl ether (20mL) in the 250mL three-necked bottle, a small amount of iodine grain.Be heated to 30 ℃, drip in the reaction solution a small amount of bromocyclopentane (
3) diethyl ether solution, heating causes reaction, after the iodine decoloration, stirs lower the dropping
3The ether of (8.94g, 60mmol) (15mL) solution drip to be finished and to be warming up to 37 ℃ of backflow 20min, cooling down to 0 ~ 5 ℃.Gradation adds
2(3g, 20mmol) adds and adds the 40mL anhydrous diethyl ether, is warming up to 30 ℃, stirs 10h, adds hydrochloric acid (30mL, 4 mol/L) to be stirred to solid entirely molten, tells ether layer, and water layer extracts three times with ether (20mL, 20mL, 10mL).The combined ether layer, with 10% aqueous sodium carbonate (60mL, 40mL) extracting twice, combining water layer transfers to pH 1 ~ 2 with concentrated hydrochloric acid, has faint yellow solid to separate out, and is standing, suction filtration, filter cake washing, the dry light yellow solid crude product that gets
5(2.6g), mp146 ~ 150 ℃.Crude product (2.6g), methylene dichloride (7.8mL) are added in the 50mL three-necked bottle lower making beating 15 min that reflux, cooling, suction filtration, filter cake washed with dichloromethane, drying gets white solid 5(2g, 45.5%) 153 ~ 154 ℃ of mp; MS (m/z): 219(M-H
+);
1H NMR (CDCl
3) δ: 1.31-1.72, (m, 8H), 2.88-2.99 (m, 1H), 7.26-7.38,7.65-7.68 (m, 5H).
α-cyclopentyl methyl mandelate (6)
Add in the 50mL three-necked bottle
5(4g, 18mmol), methyl alcohol (20mL), tosic acid (0.4g), be stirred to entirely molten, temperature rising reflux 20h.Stopped reaction, the reaction solution evaporated under reduced pressure adds entry (10mL), transfer to pH 8 ~ 9 with 10% aqueous sodium carbonate, with normal hexane (10mL * 2) extraction, organic phase anhydrous sodium sulfate drying, concentrating under reduced pressure gets faint yellow oily thing 6(2.6g, 61.7%).MS?(m/z)：235（M+H
+）。
Methyl-3-(cyclopentyl hydroxybenzene acetoxyl group) tetramethyleneimine (8)
Be equipped with in the 100mL three-necked bottle of water distilling apparatus and add sodium hydride (0.04g, 1.7mmol), normal hexane (20mL) adds under stirring
6(1.8g, 18mmol), the distillation that heats up when having cut to steam, drips
7The normal hexane of (3.5g, 15mmol) (20mL) solution drips complete being heated to and refluxes, remained in reaction process that fraction evenly distillates, and minutes three times add sodium hydride (0.1g, 4.3mmol), every minor tick 1h constantly adds normal hexane simultaneously to keep quantity of solvent constant.TLC[developping agent: sherwood oil-acetone (5:1)] to monitor to the disappearance of raw material point, stopped reaction is cooled to 25 ℃, add hydrochloric acid (20mL, 4 mol/L) to stir, suction filtration, filtrate is divided water-yielding stratum, and organic layer adds hydrochloric acid (10mL, 4 mol/L) extraction again, combining water layer transfers to pH 8 ~ 9 with 10% aqueous sodium carbonate, separates out oily matter, with ether (20mL, 10mL) extraction, combining extraction liquid, anhydrous sodium sulfate drying, the evaporated under reduced pressure solvent gets light yellow oil 8(3.4g, 75%).MS?(m/z)：304(M+H
+)。
Glycopyrronium Bromide(
1)
Add in the 100mL three-necked bottle
8The butanone of (4.6g, 15mmol) (20mL) solution drips monobromethane (2.9g under 0 ~ 5 ℃, butanone 30mmol) (5 mL) solution, dropwise, continue stirring reaction 15min, the adularescent solid is separated out, the standing 36h of room temperature, suction filtration, the fully dry crude product that gets of filter cake gets white powder crystallization 1(3.9g twice through the butanone recrystallization, 66%) 191 ~ 193 ℃ of chromatographic purities 99.8% of mp [HPLC method, moving phase: 1mol/L acetic acid triethylamine-acetonitrile-water (1:150:49); Detect wavelength: 230nm, area normalization method is measured].MS?m/z:?318(M-Br
-)；
1HNMR(CD
3OD)?δ:1.33~1.38(m,?2H),?1.55~1.70(m,?6H),?2.11~2.21(m,?1H),?2.67~2.80?(m,?1H),?3.02(m,?1H),?3.06(s,?3H),?3.23(s,?3H),?3.59~3.71(m,?3H),?3.90(dd,?
J=13.8,?1H),?5.47(m,?1H),?7.27(t,?1H),?7.35(t,?2H),?7.62(dd,?2H)。
13C?NMR?(DMSO)?δ:27.0,?27.4,?28.0,?31.3,?47.8,?53.8,?54.3,?66.0,?71.3,?74.6,?81.1,?126.9,?128.7,?129.3,143.2,175.0。
Claims (5)
1. the preparation method of a muscarinic receptor antagonist Glycopyrronium Bromide, it is characterized in that: benzoylformic acid makes α-cyclopentyl methyl mandelate through grignard reaction, esterification, then with
N-methylpyrrolidin-3-alcohol makes Glycopyrronium Bromide through transesterify, quaterisation, and its reaction formula is as follows:
。
2. method according to claim 1, it is characterized in that: benzoylformic acid (2): bromocyclopentane (3): magnesium is 1:1:1 ~ 1:5:1, makes compound α-cyclopentyl amygdalic acid (5).
3. method according to claim 1, it is characterized in that: as solvent, sodium hydride is catalyzer to intermediate (6), reacts under reflux conditions, constantly steams the methyl alcohol of generation in reaction with normal hexane, reaction.
4. method according to claim 1, it is characterized in that: prepared Glycopyrronium Bromide (1) is used butanone, and acetone is refining.
5. method according to claim 2 is characterized in that: prepared α-cyclopentyl amygdalic acid (
5)Use methylene dichloride, ethylene dichloride, butanone is refining.
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Cited By (8)
| 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 |
| CN105175304A (en) * | 2013-11-13 | 2015-12-23 | 李兴惠 | Cholinolytic drug glycopyrronium bromide and composition |
| CN107129439A (en) * | 2016-02-26 | 2017-09-05 | 中国科学院大连化学物理研究所 | A kind of compound, muscarine m receptor antagonist, composition and application |
| CN107879962A (en) * | 2017-12-22 | 2018-04-06 | 安徽德信佳生物医药有限公司 | A kind of preparation method of glycopyrronium bromide |
| WO2018154597A1 (en) * | 2017-02-22 | 2018-08-30 | Gbr Laboratories Pvt. Ltd. | Process for synthesis of glycopyrronium bromide |
| CN108976114A (en) * | 2017-06-05 | 2018-12-11 | 上海奥博生物医药技术有限公司 | A kind of purification process of glycopyrronium bromide intermediate 2- cyclopenta -2-Hydroxyphenyl Acetic Acid |
| CN113234003A (en) * | 2021-04-23 | 2021-08-10 | 广东嘉博制药有限公司 | Glycopyrronium bromide and preparation method thereof |
| CN115093355A (en) * | 2022-06-29 | 2022-09-23 | 河南农业大学 | Preparation method of pyrrole ester compound |
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2011
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| US2956062A (en) * | 1959-02-26 | 1960-10-11 | Robins Co Inc A H | Esters of amino alcohols |
| US3381017A (en) * | 1965-06-04 | 1968-04-30 | Syntex Corp | Production of carbinols employing cyclopentadienyl or lower alkyl substituted cyclopentadienyl grignard reagents and hydrogenation |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105175304A (en) * | 2013-11-13 | 2015-12-23 | 李兴惠 | Cholinolytic drug glycopyrronium bromide and composition |
| CN103819384A (en) * | 2013-12-05 | 2014-05-28 | 广东嘉博制药有限公司 | Preparation method of glycopyrronium bromide |
| CN107129439A (en) * | 2016-02-26 | 2017-09-05 | 中国科学院大连化学物理研究所 | A kind of compound, muscarine m receptor antagonist, composition and application |
| WO2018154597A1 (en) * | 2017-02-22 | 2018-08-30 | Gbr Laboratories Pvt. Ltd. | Process for synthesis of glycopyrronium bromide |
| CN108976114A (en) * | 2017-06-05 | 2018-12-11 | 上海奥博生物医药技术有限公司 | A kind of purification process of glycopyrronium bromide intermediate 2- cyclopenta -2-Hydroxyphenyl Acetic Acid |
| CN107879962A (en) * | 2017-12-22 | 2018-04-06 | 安徽德信佳生物医药有限公司 | A kind of preparation method of glycopyrronium bromide |
| CN107879962B (en) * | 2017-12-22 | 2021-06-15 | 安徽德信佳生物医药有限公司 | Preparation method of glycopyrronium bromide |
| CN113234003A (en) * | 2021-04-23 | 2021-08-10 | 广东嘉博制药有限公司 | Glycopyrronium bromide and preparation method thereof |
| CN113234003B (en) * | 2021-04-23 | 2024-02-02 | 广东嘉博制药有限公司 | Glycopyrronium bromide and preparation method thereof |
| CN115093355A (en) * | 2022-06-29 | 2022-09-23 | 河南农业大学 | Preparation method of pyrrole ester compound |
| CN115093355B (en) * | 2022-06-29 | 2024-06-04 | 河南农业大学 | Preparation method of pyrrole ester compound |
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Application publication date: 20130619 |