A kind of method for preparing Glycopyrronium Bromide
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%)