CN103819384A - Preparation method of glycopyrronium bromide - Google Patents
Preparation method of glycopyrronium bromide Download PDFInfo
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a preparation method of glycopyrronium bromide, which comprises the following steps that 1) a dimethylformamide solution dissolved with a-cyclopentyl mandelic acid is pretreated via an excessive CDI (carbonyldiimidazole) condensing agent; 1-methyl-3-pyrrolidinol is added; ester exchange reaction is performed; the reaction is terminated via purified water; an intermediate is obtained; 2) the intermediate is extracted via an organic solvent and then washed via the purified water; 3) the intermediate after Step 2) and methyl bromide perform quaterisation in a polar solvent; suction filtration is performed; a crude glycopyrronium bromide product is obtained; and 4) the crude glycopyrronium bromide product is added to an organic solution for recrystallization; and a finished glycopyrronium bromide product is obtained. The method has the characteristics of simple and convenient production operation, low production cost, high production efficiency, excellent product quality, low pollution, high safety and the like; and the obtained product meets a drug quality standard and a clinical application requirement.
Description
Technical field
The present invention relates to medical synthesis technical field, be specifically related to a kind of preparation method of Glycopyrronium Bromide of improvement.
Background technology
Glycopyrronium Bromide (Glycopyrronium Bromide) is a kind of quaternary amines Antimuscarinic type choline medicine, is researched and developed, and go on the market in the U.S. in nineteen eighty-two by SHIONOGI INC company of the U.S..This medicine has successively been made into the formulation such as tablet, injection since listing, is applicable to the clinical treatment of duodenal ulcer, chronic gastritis, gastritis supersecretion and anesthesia surgery glandular secretion management.Meanwhile, clinical study shows, Glycopyrronium Bromide is higher than the security of conventional anticholinergic agent coromegine, suppresses the stronger anticholinergic agent of glandular secretion effect.
In recent years, along with the sustainable development of domestic medicinal career, clinician more pays close attention to for the clinical advantage of Glycopyrronium Bromide, the domestic clinical demand for Glycopyrronium Bromide also highlights day by day, therefore, have easy to operate, pollute little, productive rate is high and the property of medicine safely etc. the preparation method of the Glycopyrronium Bromide of feature become people's research object, and the research of this kind of method is conducive to promote the suitability for industrialized production of Glycopyrronium Bromide, can meet market and people's demand.
The preparation method of existing Glycopyrronium Bromide mainly contains following several:
The preparation method of the Glycopyrronium Bromide of, announcing in U.S. Pat 2956062 or US 2009005577, the concrete synthetic route of the method is as follows:
The method is take a-cyclopentyl amygdalic acid as starting raw material, first carry out esterification and generate methyl 2-cyclopentyl-2-hydroxy-2-phenylacetate, in normal heptane solvent, adopt sodium Metal 99.5 or sodium hydride as alkali again, carry out transesterification reaction with 1-methyl-3-pyrrolidinol, obtain midbody product, after purified, in ethyl acetate solvent, carry out quaterisation with monobromethane, make Glycopyrronium Bromide crude product, through butanone and ethyl acetate mixed solvent recrystallization, make highly finished product Glycopyrronium Bromide again.Because transesterification reaction in method need be used sodium Metal 99.5 or sodium hydride, belong to inflammable and explosive substances, easily cause potential safety hazard.The intermediate of the method gained easily causes reversible exogenous mental disorder simultaneously, and when purifying, operational requirement is high, security risk is large, is unfavorable for suitability for industrialized production.
Two, Changde Municipal Dongting Pharmaceutical Factory is published in the preparation method of the Glycopyrronium Bromide of (medicine industry, 3,1974, p8 ~ 10) on medicine industry magazine, and the concrete synthetic route of the method is as follows:
The method is take vinylbenzene as starting raw material, do acid catalyst esterification, cyclopentadiene and the replacement of monobromethane 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, finally make crude product Glycopyrronium Bromide by quaterisation.But not only reactions steps is many for the method, productive rate is low, the security hidden trouble that simultaneously also uses sodium Metal 99.5 to bring in unresolved preparation process, is therefore not suitable for the suitability for industrialized production of Glycopyrronium Bromide.Although this factory was (document medicine industry, 3 in 1979 subsequently, 1979, p10 ~ 12) this synthetic route is improved, but this time improvement just substitutes vinylbenzene as starting raw material take phenyl glyoxilic acid methyl ester, other subsequent reactions is not reformed, therefore defect is still obvious in synthetic.
Summary of the invention
The object of the invention is to propose a kind of preparation method of Glycopyrronium Bromide, the feature such as the method has that production operation is easy, low production cost, production efficiency are high, good quality of product, pollution are little and security is high.
In order to solve prior art problem, the present invention is achieved through the following technical solutions:
A preparation method for Glycopyrronium Bromide, the method comprises the following steps:
1) first adopt excessive CDI condensing agent to carry out pre-treatment to the dimethyl formamide solution that is dissolved with a-cyclopentyl amygdalic acid, carry out transesterification reaction after adding 1-methyl-3-pyrrolidinol, then adopt purified water termination reaction, obtain intermediate;
2) adopt organic solvent to extract intermediate, then wash by purified water;
3) by through step 2) intermediate and monobromethane afterwards carry out quaterisation in polar solvent, obtains the thick product of Glycopyrronium Bromide after suction filtration;
4) thick Glycopyrronium Bromide product is added in organic solution and carries out recrystallization, obtain Glycopyrronium Bromide finished product.
It is the racemic modification Glycopyrronium Bromide of enrichment (3R, 2S) and (3S, 2R) through the Glycopyrronium Bromide finished product of step 4) gained.
Intermediate described in step 1) is α-cyclopentyl-α-phenyl-Alpha-hydroxy acetic acid-N-methyl-tetramethyleneimine ester.
Pretreated temperature described in step 1) is 18 ~ 40 ℃, and the time is 0.5 ~ 2.0h.
The temperature of reaction of transesterification reaction described in step 1) is 18 ~ 150 ℃, and the reaction times is 1 ~ 72h.
Step 2) described in the temperature of reaction of quaterisation be-20 ~ 0 ℃, the reaction times is 1 ~ 5h.
Step 2) described in organic solvent be any one or several combination in toluene, t-butyl methyl ether, Virahol, n-propyl alcohol and butanone.
Polar solvent described in step 3) is propyl alcohol or ketone.
Organic solvent described in step 4) is any one or several combination in methyl alcohol, propyl alcohol and ketone.
The present invention is optimized transesterification reaction in Glycopyrronium Bromide synthetic route, has realized a step transesterification reaction of starting raw material a-cyclopentyl amygdalic acid and 1-methyl-3-pyrrolidinol, has replaced polystep reaction, has simplified technical process, has improved production efficiency; Meanwhile, the present invention has also avoided using inflammable and explosive metal or low molecular hydrocarbon material, has effectively made up the security flaw in Glycopyrronium Bromide production process, has reduced production cost; In addition, the purity of products obtained therefrom of the present invention is good, and quality product is high, meets drug standard, meets clinical application demand.
Embodiment
The present invention has disclosed a kind of preparation method of Glycopyrronium Bromide, and the method comprises the following steps:
1) first adopt excessive CDI condensing agent to carry out pre-treatment to the dimethyl formamide solution that is dissolved with a-cyclopentyl amygdalic acid, pretreated temperature is 18 ~ 40 ℃, and the time is 0.5 ~ 2.0h; Then after adding 1-methyl-3-pyrrolidinol, carry out transesterification reaction, the temperature of reaction of transesterification reaction is 18 ~ 150 ℃, and the reaction times is 1 ~ 72h; Adopt purified water termination reaction again, obtain intermediate, intermediate is α-cyclopentyl-α-phenyl-Alpha-hydroxy acetic acid-N-methyl-tetramethyleneimine ester;
2) adopt organic solvent to extract intermediate, described organic solvent is toluene, t-butyl methyl ether, Virahol, n-propyl alcohol or butanone, mentioned organic solvent a kind of use separately, also can use by multiple combination, the technology that described extraction process is well known to those skilled in the art, then wash by purified water;
3) by through step 2) intermediate and monobromethane afterwards carry out quaterisation in polar solvent, the temperature of reaction of quaterisation is-20 ~ 0 ℃, and the reaction times is 1 ~ 5h, and described polar solvent is propyl alcohol or ketone, carry out again suction filtration, obtain the thick product of Glycopyrronium Bromide;
4) thick Glycopyrronium Bromide product is added in organic solution and carries out recrystallization, obtain Glycopyrronium Bromide finished product, the Glycopyrronium Bromide of gained is the racemic modification Glycopyrronium Bromide of enrichment (3R, 2S) and (3S, 2R); Described organic solvent is any one or several combination in methyl alcohol, propyl alcohol and ketone.
The above-mentioned CDI condensing agent of mentioning is N, and N '-carbonyl dimidazoles, can promote transesterification reaction, and can better obtain intermediate is α-cyclopentyl-α-phenyl-Alpha-hydroxy acetic acid-N-methyl-tetramethyleneimine ester.
The present invention is optimized transesterification reaction in Glycopyrronium Bromide synthetic route, has realized a step transesterification reaction of starting raw material a-cyclopentyl amygdalic acid and 1-methyl-3-pyrrolidinol, has replaced polystep reaction, has simplified technical process, has improved production efficiency; Meanwhile, the present invention has also avoided using inflammable and explosive metal or low molecular hydrocarbon material, has effectively made up the security flaw in Glycopyrronium Bromide production process, has reduced production cost; In addition, the purity of products obtained therefrom of the present invention is good, and quality product is high, meets drug standard, meets clinical application demand.
For those skilled in the art's understanding, below by specific embodiment, the present invention is described in further detail.
Embodiment 1
A preparation method for Glycopyrronium Bromide, the method comprises the following steps:
1) the a-cyclopentyl amygdalic acid of 150g is dissolved in the dimethyl formamide (DMF) of 1kg, dissolves and be placed in 5L dry reaction bottle, add the N of 135g, N '-carbonyl dimidazoles stirs 2.0h at 18 ℃; Then the 1-methyl-3-pyrrolidinol that adds 85g is heated to 60 ℃ in 1h, maintains and stirs 18h, cooling, adds 1kg purified water termination reaction, obtains intermediate a-cyclopentyl-a-phenyl-a-oxyacetic acid-N-methyl-tetramethyleneimine ester;
2) add 1kg toluene, the intermediate of step 1) reaction gained is extracted, then adopt purified water washing 3 times;
3) adopt to revolve steam concentrating under reduced pressure to through step 2) intermediate after treatment concentrates, and is concentrated into concentration and is 50% toluene solution, adds the dilution of 600g n-propyl alcohol, and the solution after dilution is cooled to 0 ℃; Add the monobromethane of 85g, under 0 ℃ of condition, stir after 2h, continue to stir and be heated to 60 ℃, stopped reaction; Be cooled to after room temperature, suction filtration, filtration cakes torrefaction, obtains 123g Glycopyrronium Bromide crude product;
4) whole crude products being added to 1.23kg weight percent is that the n-propyl alcohol of 0.1%wt carries out recrystallization, obtains the highly purified Glycopyrronium Bromide of 115g.Yield is 84%, through HPLC check, its purity >99.0%.Product is carried out to ultimate analysis, nmr analysis and mass spectroscopy, all show that product prepared by the inventive method is Glycopyrronium Bromide finished product.
Embodiment 2
A preparation method for Glycopyrronium Bromide, the method comprises the following steps:
1) the a-cyclopentyl amygdalic acid of 600g is dissolved in the dimethyl formamide (DMF) of 4kg, dissolves and be placed in 20L dry reaction bottle, add the N of 540g, N '-carbonyl dimidazoles stirs 1.0h under room temperature; Then add 1-methyl-3-pyrrolidinol of 340g, under room temperature, continue to stir 72h, cooling, add 4kg purified water termination reaction, obtain intermediate a-cyclopentyl-a-phenyl-a-oxyacetic acid-N-methyl-tetramethyleneimine ester;
2) add 4kg t-butyl methyl ether, the intermediate of step 1) reaction gained is extracted, adopt purified water washing 3 times;
3) adopt to revolve steam concentrating under reduced pressure to through step 2) intermediate after treatment concentrates, and is concentrated into concentration and is 50% toluene solution, then adds the dilution of 2.4kg n-propyl alcohol, the solution after dilution is placed under-20 ℃ of conditions; Add the monobromethane of 340g, under-20 ℃ of conditions, stir after 2h, continue to stir and be heated to 60 ℃, stopped reaction; Be cooled to after room temperature, suction filtration, filtration cakes torrefaction, obtains 521g Glycopyrronium Bromide crude product;
4) whole crude products being added to 1.23kg weight percent is that the n-propyl alcohol of 0.1%wt carries out recrystallization, obtains the highly purified Glycopyrronium Bromide finished product of 505g.Productive rate is 92%, through HPLC check, its purity >99.0%.Product is carried out to ultimate analysis, nmr analysis and mass spectroscopy, all show that product prepared by the inventive method is Glycopyrronium Bromide finished product.
Embodiment 3
A preparation method for Glycopyrronium Bromide, the method comprises the following steps:
1) the a-cyclopentyl amygdalic acid of 600g is dissolved in the dimethyl formamide (DMF) of 4kg, dissolves and be placed in 20L dry reaction bottle, add the N of 540g, N '-carbonyl dimidazoles stirs 0.5h at 40 ℃; Then add 1-methyl-3-pyrrolidinol of 340g, at 150 ℃, continue to stir 1h, cooling, add 4kg purified water termination reaction, obtain intermediate a-cyclopentyl-a-phenyl-a-oxyacetic acid-N-methyl-tetramethyleneimine ester;
2) add 4kg t-butyl methyl ether, the intermediate of step 1) reaction gained is extracted, adopt purified water washing 3 times;
3) adopt to revolve steam concentrating under reduced pressure to through step 2) intermediate after treatment concentrates, and is concentrated into concentration and is 50% toluene solution, then adds the dilution of 2.4kg n-propyl alcohol, the solution after dilution is placed under-10 ℃ of conditions; Add the monobromethane of 340g, under-10 ℃ of conditions, stir after 5h, continue to stir and be heated to 60 ℃, stopped reaction; Be cooled to after room temperature, suction filtration, filtration cakes torrefaction, obtains 513g Glycopyrronium Bromide crude product;
4) whole crude products being added to 1.23kg weight percent is that the n-propyl alcohol of 0.1%wt carries out recrystallization, obtains the highly purified Glycopyrronium Bromide finished product of 486g.Productive rate is 91%%, through HPLC check, its purity >99.0%.
Glycopyrronium Bromide finished product to embodiment 1 ~ 3 gained carries out ultimate analysis, nmr analysis and mass spectroscopy, and analytical results is as follows:
Ultimate analysis:
The Glycopyrronium Bromide structural identification reference substance product in contrast that adopt Nat'l Pharmaceutical & Biological Products Control Institute to provide.Acquired results is as shown in table 1:
| Element | Sample measured value | Reference substance measured value | Theoretical value |
| C | 57.05 | 57.11 | 57.29 |
| H | 7.11 | 5.19 | 7.09 |
| N | 3.45 | 3.50 | 3.52 |
| Br | 19.99 | 19.87 | 20.06 |
Table 1: results of elemental analyses.
Structural identification magnetic spectrum is analyzed:
1h-NMR spectrum elucidation
According to COSY spectrum and heavy water exchange spectrum, in conjunction with HMQC spectrum, HMBC spectrum and DEPT spectrum, can belong to the 1H spectrum of Glycopyrronium Bromide sample:
H spectrum shows 16 groups of hydrogen, is respectively 2: 2: 1: 1: 1: 1: 1: 1: 1: 3: 3: 1: 1: 1: 6 by low to the integration ratio of High-Field hydrogen: 2, conform to the structure of Glycopyrronium Bromide.
δ 7.60 place's hydrogen are one group of doublet, and proton number is 2; COSY composes demonstration, and this place's hydrogen and δ 7.36 hydrogen, δ 7.27 hydrogen are relevant; Be attributed to 14,14 ' phenyl ring virtue hydrogen.
δ 7.36 place's hydrogen are one group of double doublet, and proton number is 2; COSY composes demonstration, and this place's hydrogen is relevant with δ 7.60 hydrogen 14,14 '; Be attributed to 15,15 ' phenyl ring virtue hydrogen.
δ 7.27 place's hydrogen are one group of doublet, and proton number is 1; COSY composes demonstration, and this place's hydrogen is relevant with δ 7.60 hydrogen 14,14 '; Be attributed to 16 phenyl ring virtue hydrogen.
δ 5.85 place's hydrogen be one group unimodal, proton number is 1; After heavy water exchange, this peak disappears substantially; Should be reactive hydrogen, be attributed to 17 for hydroxyl hydrogen.
δ 5.38 place's hydrogen are one group of multiplet, and proton number is 1; COSY composes demonstration, and this place's hydrogen is relevant to δ 3.92 hydrogen; Be attributed to 3 precedence methyl hydrogen.
δ 3.92, δ 3.64 place's hydrogen are respectively one group of double doublet, and proton number is 1; COSY composes demonstration, and these two groups of hydrogen are relevant; HMQC spectrum and the demonstration of DEPT spectrum, these two groups of hydrogen are relevant to same secondary carbon; Be attributed to two hydrogen 2b and 2a on 2 methylene radical.
δ 3.74, δ 3.57 place's hydrogen are respectively one group of multiplet, and proton number is 1; COSY composes demonstration, and these two groups of hydrogen are relevant; HMQC spectrum and the demonstration of DEPT spectrum, these two groups of hydrogen are relevant to same secondary carbon; Be attributed to two hydrogen 5b and 5a on 5 methylene radical.
δ 3.22 place's hydrogen be one group unimodal, proton number is 3; Be attributed to 1(1 ') position methyl hydrogen.
δ 3.13 place's hydrogen be one group unimodal, proton number is 1; Be attributed to 1 ' (1) methyl hydrogen.
δ 2.92 place's hydrogen are one group of multiplet, and proton number is 1; Be attributed to 8 precedence methyl hydrogen.
δ 2.66, δ 2.08 place's hydrogen are respectively one group of multiplet, and proton number is 1; COSY composes demonstration, and these two groups of hydrogen are relevant; HMQC spectrum and the demonstration of DEPT spectrum, these two groups of hydrogen are relevant to same secondary carbon; Be attributed to two hydrogen 4b and 4a on 4 methylene radical.
δ 1.6 ~ 1.2 place's hydrogen are one group of multiple cutting edge of a knife or a sword, and proton number is 8; Be attributed to the methylene radical hydrogen on 9,10,11,12.
13c-NMR spectrum elucidation
In Glycopyrronium Bromide molecular structure, there are 19 carbon, wherein 14 and 14 ', 15 and 15 ', 9 and 12,10 and 11 is symmetrical carbon, and the demonstration of the 13C of this product spectrum has 15 groups of carbon peaks, and this product shows 17 groups of carbon peaks, this is owing to may having optically active isomer in sample, 9 and 12,10 and 11 chemical shift differences of optically active isomer cause, this conforms to Glycopyrronium Bromide molecular structure.According to DEPT spectrum, HMQC spectrum and HMBC spectrum, resolve as follows:
The demonstration of DEPT spectrum contains 2 groups of primary carbon peaks, and this conforms to Glycopyrronium Bromide molecular structure.The wherein primary carbon peak of δ 52.54, in HMQC spectrum to δ 3.22 hydrogen 1(1 ') relevant, be attributed to 1(1 ') a methyl carbon; HMBC composes demonstration, and this carbon peak and δ 3.13 hydrogen 1 ' (1), δ 3.57 hydrogen 5a, δ 3.92 hydrogen 2b distant relations confirm that ownership is correct.
The primary carbon peak of δ 52.01, relevant to δ 3.13 hydrogen 1 ' (1) in HMQC spectrum, be attributed to 1 ' (1) methyl carbon; HMBC composes demonstration, this carbon peak and δ 3.22 hydrogen 1(1 '), δ 3.64 hydrogen 2b, δ 3.57 hydrogen 5a, δ 3.92 hydrogen 2b distant relations, confirm that ownership is correct.
DEPT spectrum shows 7 groups of secondary carbon peaks and exists, and this conforms to Glycopyrronium Bromide molecular structure.Wherein one of δ 69.18 group of secondary carbon peak, simultaneously relevant to δ 3.92 hydrogen 2b, δ 3.64 hydrogen 2a in HMQC spectrum, is attributed to 2 mesomethylene carbon; HMBC composes demonstration, and this carbon peak and δ 3.22 hydrogen 1 (1 '), δ 3.13 hydrogen 1 ' (1), δ 3.57 hydrogen 5a, δ 2.66 hydrogen 4b, δ 3.74 hydrogen 5b distant relations confirm that ownership is correct.
One group of secondary carbon peak of δ 63.82, simultaneously relevant to δ 3.74 hydrogen 5b, δ 3.57 hydrogen 5a in HMQC spectrum, be attributed to 5 mesomethylene carbon; HMBC composes demonstration, and this carbon peak and δ 3.22 hydrogen 1 (1 '), δ 3.13 hydrogen 1 ' (1), δ 3.57 hydrogen 5a, δ 2.08 hydrogen 4a, δ 2.66 hydrogen 4b, δ 5.38 hydrogen 3, δ 3.64 hydrogen 2a, δ 3.92 hydrogen 2b distant relations confirm that ownership is correct.
One group of secondary carbon peak of δ 29.62, simultaneously relevant to δ 2.66 hydrogen 4b, δ 2.08 hydrogen 4a in HMQC spectrum, be attributed to 4 mesomethylene carbon; HMBC composes demonstration, and this carbon peak and δ 3.57 hydrogen 5a, δ 3.64 hydrogen 2a, distant relation confirm that ownership is correct.
The secondary carbon peak of δ 26.55,25.54 is attributed to respectively 10,11 methyl carbon of the optically active isomer existing in molecule.
The secondary carbon peak of δ 26.01, δ 25.95 is attributed to respectively 9,12 methyl carbon of the optically active isomer existing in molecule.
DEPT spectrum shows 5 groups of tertiary carbon peaks and exists, and conforms to Glycopyrronium Bromide molecular structure.The wherein tertiary carbon peak of δ 127.92 to δ 7.36 hydrogen 15,15 ' relevant, is attributed to 15,15 ' methine carbon in HMQC spectrum.
δ 127.21 tertiary carbon peaks, relevant to δ 7.27 hydrogen 16 in HMQC spectrum, be attributed to 16 methine carbons; HMBC composes demonstration, and this carbon peak and δ 7.60 hydrogen 14,14 ' distant relation confirm that ownership is correct.
The tertiary carbon peak of δ 125.60 to δ 7.60 hydrogen 14,14 ' relevant, is attributed to 14,14 ' methine carbon in HMQC spectrum; HMBC composes demonstration, and this carbon peak and δ 7.27 hydrogen 16 distant relations confirm that ownership is correct.
The tertiary carbon peak of δ 72.64, relevant to δ 5.38 hydrogen 3 in HMQC spectrum, be attributed to 3 methine carbons; HMBC composes demonstration, and this carbon peak and δ 2.08 hydrogen 4a, δ 2.66 hydrogen 4b, δ 3.64 hydrogen 2a, δ 3.74 hydrogen 5b distant relations confirm that ownership is correct.
The tertiary carbon peak of δ 46.58, relevant to δ 2.92 hydrogen 8 in HMQC spectrum, be attributed to 8 methine carbons; HMBC composes demonstration, and this carbon peak and δ 5.85 hydrogen 17, δ 1.21 hydrogen, δ 1.61 hydrogen distant relations confirm that ownership is correct.
DEPT spectrum shows 3 groups of quaternary carbon peaks and exists, and conforms to Glycopyrronium Bromide molecular structure.The wherein quaternary carbon peak of δ 173.37 shows and δ 5.85 hydrogen 17, δ 5.38 hydrogen 3 distant relations in HMBC spectrum, is attributed to 6 carbonyl carbon.
The quaternary carbon peak of δ 142.07 shows and δ 5.85 hydrogen 17, δ 7.36 hydrogen 15,15 ' distant relations in HMBC spectrum, is attributed to 13 quaternary carbons.
The quaternary carbon peak of δ 79.20 shows and δ 7.60 hydrogen 14,14 ', δ 5.85 hydrogen 17, δ 1.21 hydrogen distant relations in HMBC spectrum, is attributed to 7 quaternary carbons.
MS: m/z(M+) 318(100%), the grand bromine ammonium base of dative molecular weight is consistent, meets Glycopyrronium Bromide structure.
Hence one can see that, and the racemic modification Glycopyrronium Bromide that the prepared Glycopyrronium Bromide finished product of the present invention is enrichment (3R, 2S) and (3S, 2R), and good quality of product, meet drug standard, meets clinical application demand.
The content of mentioning in above-described embodiment is not limitation of the invention, is not departing under the prerequisite of inventive concept of the present invention, and any apparent replacement is all within protection scope of the present invention.
Claims (9)
1. a preparation method for Glycopyrronium Bromide, the method comprises the following steps:
1) first adopt excessive CDI condensing agent to carry out pre-treatment to the dimethyl formamide solution that is dissolved with a-cyclopentyl amygdalic acid, carry out transesterification reaction after adding 1-methyl-3-pyrrolidinol, then adopt purified water termination reaction, obtain intermediate;
2) adopt organic solvent to extract intermediate, then wash by purified water;
3) by through step 2) afterwards intermediate and monobromethane in polar solvent, carry out quaterisation, after suction filtration, obtain the thick product of Glycopyrronium Bromide;
4) thick Glycopyrronium Bromide product is added in organic solution and carries out recrystallization, obtain Glycopyrronium Bromide finished product.
2. the preparation method of Glycopyrronium Bromide according to claim 1, is characterized in that: be the racemic modification Glycopyrronium Bromide of enrichment (3R, 2S) and (3S, 2R) through the Glycopyrronium Bromide finished product of step 4) gained.
3. the preparation method of Glycopyrronium Bromide according to claim 2, is characterized in that: the intermediate described in step 1) is α-cyclopentyl-α-phenyl-Alpha-hydroxy acetic acid-N-methyl-tetramethyleneimine ester.
4. the preparation method of Glycopyrronium Bromide according to claim 3, is characterized in that: pretreated temperature described in step 1) is 18 ~ 40 ℃, and the time is 0.5 ~ 2.0h.
5. the preparation method of Glycopyrronium Bromide according to claim 4, is characterized in that: the temperature of reaction of transesterification reaction described in step 1) is 18 ~ 150 ℃, and the reaction times is 1 ~ 72h.
6. the preparation method of Glycopyrronium Bromide according to claim 5, is characterized in that: step 2) described in the temperature of reaction of quaterisation be-20 ~ 0 ℃, the reaction times is 1 ~ 5h.
7. according to the preparation method of the Glycopyrronium Bromide described in any one in claim 1 ~ 6, it is characterized in that: step 2) described in organic solvent be any one or several combination in toluene, t-butyl methyl ether, Virahol, n-propyl alcohol and butanone.
8. according to the preparation method of the Glycopyrronium Bromide described in any one in claim 1 ~ 6, it is characterized in that: the polar solvent described in step 3) is propyl alcohol or ketone.
9. according to the preparation method of the Glycopyrronium Bromide described in any one in claim 1 ~ 6, it is characterized in that: the organic solvent described in step 4) is any one or several combination in methyl alcohol, propyl alcohol and ketone.
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| CN107915666A (en) * | 2016-10-09 | 2018-04-17 | 四川海思科制药有限公司 | A kind of glycopyrronium bromide compound |
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| CN113461585A (en) * | 2021-07-12 | 2021-10-01 | 安徽普利药业有限公司 | Synthesis process of glycopyrronium bromide |
| 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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| CN107304178A (en) * | 2016-04-21 | 2017-10-31 | 辽宁药联制药有限公司 | A kind of preparation method of muscarinic receptor antagonist glycopyrronium bromide chiral enantiomer |
| CN107304178B (en) * | 2016-04-21 | 2020-03-27 | 辽宁药联制药有限公司 | Preparation method of muscarinic receptor antagonist glycopyrronium bromide chiral enantiomer |
| CN107915666A (en) * | 2016-10-09 | 2018-04-17 | 四川海思科制药有限公司 | A kind of glycopyrronium bromide compound |
| 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 |
| 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 |
| CN113461585A (en) * | 2021-07-12 | 2021-10-01 | 安徽普利药业有限公司 | Synthesis process of glycopyrronium bromide |
| CN113461585B (en) * | 2021-07-12 | 2023-10-31 | 安徽普利药业有限公司 | Synthesis process of glycopyrronium bromide |
| CN114890997A (en) * | 2022-04-20 | 2022-08-12 | 江苏联环药业股份有限公司 | Preparation process of anticholinergic drug tiaogelium bromide |
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