CN101475497A - Method for preparing terbutaline sulphate crystal form B meeting medicinal requirements - Google Patents
Method for preparing terbutaline sulphate crystal form B meeting medicinal requirements Download PDFInfo
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- CN101475497A CN101475497A CNA2008101898577A CN200810189857A CN101475497A CN 101475497 A CN101475497 A CN 101475497A CN A2008101898577 A CNA2008101898577 A CN A2008101898577A CN 200810189857 A CN200810189857 A CN 200810189857A CN 101475497 A CN101475497 A CN 101475497A
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- bricalin
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Abstract
The invention provides a method for preparing terbutaline sulphate B crystal form. The method comprises: selecting a solvent, dissolving 1-(3,5-dibenzyloxy phenyl)-2-n-tert-butyl aminoethanol into the solvent, removing benzyl groups through hydrogenolysis by a general method, obtaining terbutaline free alkali, and adding sulfuric acid into the terbutaline free alkali to form terbutaline sulphate of crystal form B; or dissolving terbutaline sulphate of non-crystal form B into the solvent, stirring the terbutaline sulphate of the non-crystal form B in the solvent at a certain temperature until the terbutaline sulphate of the non-crystal form B is converted into the terbutaline sulphate B crystal form through dissolution and lixiviation, and reclaiming the leached terbutaline sulphate B crystal form. The method has the advantage of obtaining the terbutaline sulphate B crystal form which has stable chemical and physical properties and meets the requirements of medical preparation.
Description
Technical field
The invention belongs to medical technical field, be specifically related to α-[(uncle's fourth amino) methyl]-3,5-dihydroxybenzyl alcohol vitriol (2:1) is the preparation method of terbutaline sulphate crystal B.
Background technology
α-[(uncle's fourth amino) methyl]-3,5-dihydroxybenzyl alcohol vitriol (2:1) (this paper bricalin) is 23031-32-5 CAS number, molecular formula is (C
12H
19NO
3)
2H
2SO
4And have a following structure:
The alternative excited beta 2-adrenergic receptor of bricalin, lax bronchial smooth muscle, the oedema that suppresses the release of endogenous spasmogen and can suppress to cause by endogenous messenger and mucociliary clearance aggravation.Its bronchiectatic activity is close with husky fourth ammonia alcohol.The antiasthmatic effect of this product 2.5mg is suitable with the 25mg ephedrine.Animal or human's isolated experiment confirms that its effect to the heart β1Shou Ti is minimum, and its excitation to heart only reaches 1/100 of Racemic isoproterenol.The treatment of the bronchospasm when bricalin is mainly used in bronchial asthma, asthmatic bronchitis and chronic obstructive lung illness clinically.Quiet then can be suppressed the uterine contraction that spontaneous uterine contraction and pitocin cause, prevent premature etc. continuously.
Patent US3937838 has early disclosed the structure, preparation technology of compound bricalin and it clinical application as selectivity beta 2-adrenergic receptor agonist.Document (Chinese Journal of Pharmaceuticals, 1999/30) disclosed a kind ofly, be used for synthetic (aforesaid method forms the terbutaline sulphate crystal B that solvent that vitriol or treating process adopt can not obtain meeting medicinal requirements at terbutaline) of bricalin than simple synthesis method.This medicine is in clinical application, and main administering mode has: atomizing sucks, oral, injection.Research (Jaeschke R, Guyall GH, Willan A, et al.The effect of increasing doses of betaagonists on spirometry, exercise capacity, and quality of life in patients with chronic ai rflow limitation.Thorax, 1994,49:478.) showing that the atomizing inhalation is the best administering mode of beta receptor agonist, this administering mode has less heart, blood vessel side effect.Bricalin is a suspension aerosol, and this formulation at first will be carried out the micronization processes of medicine in the preparation process.For polymorph medicine, this process usually can cause the variation of crystal formation.Crystal formation is the critical nature of compound, and to the stability of medicine and product quality homogeneity, bioavailability, preparation etc. are all influential.In addition, from the dissection and the physiological structure analysis of segmental bronchus, bronchiole and lung, for medicine effectively being distributed or being deposited on above-mentioned therapentic part, the granularity that requires medicine or pastille droplet is about 5um.Excessive (greater than 10um) or too small (less than 1um) thus granularity drug deposition is lessened the curative effect at therapentic part.Studies show that the physical properties of main ingredient can exert an influence to the size of drug particle size.Furthermore, owing to differences of physical properties between each crystal formation of polymorph medicine also will impact the preparation process.Document (CRYSTAL GROWNTH﹠amp; DESIGN, 2008.Vo18.NO1 80-90) discloses bricalin and can exist with five kinds of crystal formations at least, be respectively: crystal form A, crystal form B, monohydrate, polyhydrate, acetate compound.Document author (Solubility experiments in water-ethanol mixtures) also by experiment reaches a conclusion: compare with other crystal formations of bricalin, terbutaline sulphate crystal B is to stablize crystal formation.Further specify, terbutaline sulphate crystal B is more suitable in the preparation of suspension aerosol and other formulations.Although relevant for the report of terbutaline sulphate crystal B, do not see the method for preparing terbutaline sulphate crystal B that clearly discloses up to now as yet.
In sum, need in this area a kind of easy, stable, prepare the method for the terbutaline sulphate crystal B that meets medicinal requirements efficiently.
Summary of the invention
The present invention relates to terbutaline sulphate crystal B and preparation method, this crystal formation is characterised in that the radiation with Co-K α, be positioned at about 9.9,12.9,21.5,22.7,25.0,27.6,28.9 ± 0.2 degree 2 θ powder X-ray RD peaks, can further characterize with powder X-ray RD pattern that is positioned at about 8.5,11.3,14.9,15.8,20.0,23.6 ± 0.2 degree, 2 θ or powder X-ray RD pattern substantially as shown in Figure 1.
Present method is to select a kind of solvent, and 1-(3,5 two benzyloxy phenyl)-2-tertiary butyl amido ethanol is dissolved in wherein, slough benzyl by the universal method hydrogenolysis, get the terbutaline free alkali, add the bricalin that sulfuric acid forms crystal form B again, reclaim the terbutaline sulphate crystal B that forms then;
Or, select a kind of solvent, bricalin in this solvent has low solubility, the bricalin of armorphous B is dissolved in wherein, 0 ℃ of bricalin suspension that stirs this solvent under the reflux temperature 10 minutes-100 hours, terbutaline sulphate crystal B will form, and reclaims the terbutaline sulphate crystal B that forms then.
Described solvent is the solvent orange 2 A that water and esters solvent form, and its proportion of composing is represented with the water content of this esters solvent, is about 0.03% to saturated, and the solvent orange 2 A consumption under agitation forms suspension for guaranteeing bricalin at least;
Described esters solvent is selected from ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, ethyl propionate, propyl propionate, butyl propionate, isopropyl propionate, methyl benzoate, ethyl benzoate or methyl aceto acetate or other can be used as the ester class with following structure that solvent uses:
R wherein
2Expression straight or branched alkane: R
1Represent straight or branched alkane, or contain the alkane derivatives of heteroatoms or heteroatoms replacement, or C
6-C
12Aryl, wherein the hydrogen on the aryl can be replaced by other substituting groups.
Preferably, described solvent orange 2 A is the mixed solvent of water and ethyl acetate, and its ratio is expressed as 0.03% to saturated with the ethyl acetate water content.
Preferably, 1-(3,5 two benzyloxy phenyl)-bricalin of 2-tertiary butyl amido ethanol or armorphous B and total solvent amount optimum proportion be by the bricalin 10ml of every gram 1-(3,5 two benzyloxy phenyl)-2-tertiary butyl amido ethanol or the armorphous B amount use solvent to 20ml.
Described temperature range is 0 ℃ and arrives reflux temperature that optimum temperature range is 18 ℃ to 40 ℃; Churning time is 10 minutes-100 hours, best churning time 24-36 hour.
Preferably, the method for reclaim(ed) sulfuric acid terbutaline crystal form B is for to wave solvent or dried recovered terbutaline sulphate crystal B under 50 ℃ of nitrogen gas stream under normal pressure.
Same principle, the solvent orange 2 A of aforesaid method can be used as terbutaline and become solvent in the vitriol process, also can be used as the solvent of POV terbutaline crystal form B.
In present method, the multiple mixed solvent that solvent can adopt solvent orange 2 A and solvent B to form.Described solvent B is selected from the organic solvent alkanes, ester or lipid, aromatic hydrocarbons, ethers, alcohols, halogenated hydrocarbon and DMF, DMSO or other organic solvents; The ratio of solvent orange 2 A and solvent B is 10:0～1:9, and optimum proportion is 10:0～7:3; The ratio of the bricalin of mixed solvent consumption and 1-(3,5 two benzyloxy phenyl)-2-tertiary butyl amido ethanol or armorphous B is 1ml～1000ml:1g.
Organic solvent B is made up of with arbitrary proportion one or more solvents, and wherein alkanes is selected from hexane, heptane, hexanaphthene, and sherwood oil or other can be used as the alkane that solvent uses; The ester class is selected from ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, methyl benzoate or ethyl benzoate or other can be used as ester or the grease that solvent uses; Ketone is selected from acetone, 2-butanone or pimelinketone or other can be used as the ketone that solvent uses; Aromatic hydrocarbons is selected from benzene, toluene or dimethylbenzene or other can be used as the aromatic hydrocarbons that solvent uses, ethers is selected from tetrahydrofuran (THF), ether, isopropyl ether or methyl tertiary butyl ether or other and can be used as the ether that solvent uses, and alcohols is selected from methyl alcohol, ethanol Virahol, various butanols, various amylalcohol, various hexanol or other can be used as the alcohol that solvent uses; Halogenated hydrocarbon is selected from methylene dichloride, chloroform or other can be used as the halocarbon that solvent uses.
Preferably, solvent B is one or more in acetone, benzene, tetrahydrofuran (THF), ether, ethanol, methylene dichloride, the chloroform.
Preferably, mixed solvent consists of water, ethyl acetate, solvent B (as above-mentioned, comprising acetone, benzene, tetrahydrofuran (THF), ether, ethanol, methylene dichloride, chloroform).
Preferably, the composition of solvent B in mixed solvent is less than 10%.
Preferably, the ratio 10ml of the bricalin of mixed solvent consumption and 1-(3,5 two benzyloxy phenyl)-2-tertiary butyl amido ethanol or armorphous B uses solvent to the amount of 20ml.
Described temperature range is 0 ℃ and arrives reflux temperature that optimum temperature range is 18 ℃ to 40 ℃; Churning time is 10 minutes-100 hours, best churning time 24-36 hour.
Preferably, the method for reclaim(ed) sulfuric acid terbutaline crystal form B is for to wave solvent or dried recovered terbutaline sulphate crystal B under 50 ℃ of nitrogen gas stream under normal pressure.
Same principle, the solvent of aforesaid method can be used as terbutaline and become solvent in the vitriol process, also can be used as the solvent of POV terbutaline crystal form B.
Advantage of the present invention is: by simple aforesaid method, it is stable to obtain chemistry and physical properties, the terbutaline sulphate crystal B that the fulfilling medicinal preparation requires.
Description of drawings
Fig. 1 illustrates the XRD diffractogram of terbutaline sulphate crystal B
Embodiment
By with reference to the following example of describing preparation method of the present invention in detail, further describe the present invention.One of ordinary skill in the art be it is evident that,, can implement many improvement material and method without departing from the scope of the invention.
Embodiment 1
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the aqueous ethyl acetate of 10ml (water saturation), then the gained suspension was dried to constant weight 50 ℃ of nitrogen gas stream.Get terbutaline sulphate crystal B.
Embodiment 2
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the aqueous ethyl acetate of 10ml (water semi-saturation), then the gained suspension was dried to constant weight under 50 ℃ of nitrogen gas stream.Get terbutaline sulphate crystal B.
Embodiment 3
0.5g non-B crystal formation bricalin stirred 24 hours down in 35 ℃ in the aqueous ethyl acetate of 10ml (water saturation), then the gained suspension was dried to constant weight under 50 ℃ of nitrogen gas stream.Get terbutaline sulphate crystal B.
Embodiment 4
0.5g non-B crystal formation bricalin stirred 36 hours down in 25 ℃ in the aqueous ethyl acetate of 10ml (water saturation), then the gained suspension was dried to constant weight under 50 ℃ of nitrogen gas stream.Get terbutaline sulphate crystal B.
Embodiment 5
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, acetone 1ml form, and then the gained suspension was dried to constant weight under 50 ℃ of nitrogen gas stream.Get terbutaline sulphate crystal B.
Embodiment 6.
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, benzene 1ml form, and then the gained suspension was dried to constant weight under 50 ℃ of nitrogen gas stream.Get terbutaline sulphate crystal B.
Embodiment 7
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, tetrahydrofuran (THF) 1ml form, and then the gained suspension was dried to constant weight under 50 ℃ of nitrogen gas stream.Get terbutaline sulphate crystal B.
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, ether 1ml form, and then the gained suspension was dried to constant weight under 50 ℃ of nitrogen gas stream.Get terbutaline sulphate crystal B.
Embodiment 9
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, ethanol 1ml form, and then the gained suspension was dried to constant weight under 50 ℃ of nitrogen gas stream.Get terbutaline sulphate crystal B.
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, methylene dichloride 1ml form, and then the gained suspension was dried to constant weight under 50 ℃ of nitrogen gas stream.Get terbutaline sulphate crystal B.
Embodiment 11
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, chloroform 1ml form, and then the gained suspension was dried to constant weight under 50 ℃ of nitrogen gas stream.Get terbutaline sulphate crystal B.
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the aqueous ethyl acetate of 10ml (water saturation), filter, in 50 ℃ of decompressions (but also normal pressure) drying 1 hour, again 80 ℃ of dryings 1 hour, be dried to constant weight at 120 ℃ at last, get terbutaline sulphate crystal B.
Embodiment 13
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the aqueous ethyl acetate of 5ml (water saturation), filter, in 50 ℃ of decompressions (but also normal pressure) drying 1 hour, again 80 ℃ of dryings 1 hour, be dried to constant weight at 120 ℃ at last, get terbutaline sulphate crystal B.
0.5g non-B crystal formation bricalin stirred 24 hours down in 35 ℃ in the aqueous ethyl acetate of 10ml (water saturation), filter, in 50 ℃ of decompressions (but also normal pressure) drying 1 hour, again 80 ℃ of dryings 1 hour, be dried to constant weight at 120 ℃ at last, get terbutaline sulphate crystal B.
Embodiment 15
0.5g non-B crystal formation bricalin stirred 36 hours down in 25 ℃ in the aqueous ethyl acetate of 10ml (water saturation), filter, in 50 ℃ of decompressions (but also normal pressure) drying 1 hour, again 80 ℃ of dryings 1 hour, be dried to constant weight at 12 ℃ at last, get terbutaline sulphate crystal B.
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, acetone 1ml form, filter, in dry 1 hour of 50 ℃ of decompressions (but also normal pressure), again 80 ℃ of dryings 1 hour, be dried to constant weight at 120 ℃ at last, get terbutaline sulphate crystal B.
Embodiment 17
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, benzene 1ml form, filter, in dry 1 hour of 50 ℃ of decompressions (but also normal pressure), again 80 ℃ of dryings 1 hour, be dried to constant weight at 120 ℃ at last, get terbutaline sulphate crystal B.
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, tetrahydrofuran (THF) 1ml form, filter, in dry 1 hour of 50 ℃ of decompressions (but also normal pressure), again 80 ℃ of dryings 1 hour, be dried to constant weight at 120 ℃ at last, get terbutaline sulphate crystal B.
Embodiment 19
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, ether 1ml form, filter, in dry 1 hour of 50 ℃ of decompressions (but also normal pressure), again 80 ℃ of dryings 1 hour, be dried to constant weight at 120 ℃ at last, get terbutaline sulphate crystal B.
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, ethanol 1ml form, filter, in dry 1 hour of 50 ℃ of decompressions (but also normal pressure), again 80 ℃ of dryings 1 hour, be dried to constant weight at 120 ℃ at last, get terbutaline sulphate crystal B.
Embodiment 21
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, methylene dichloride 1ml form, filter, in dry 1 hour of 50 ℃ of decompressions (but also normal pressure), again 80 ℃ of dryings 1 hour, be dried to constant weight at 120 ℃ at last, get terbutaline sulphate crystal B.
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the mixed solvent that aqueous ethyl acetate (water saturation) 9ml, chloroform 1ml form, filter, in dry 1 hour of 50 ℃ of decompressions (but also normal pressure), again 80 ℃ of dryings 1 hour, be dried to constant weight at 120 ℃ at last, get terbutaline sulphate crystal B.
Embodiment 23
With 1-(3,5 two benzyloxy phenyl)-to join the 200ml water content be in 1.7% the ethyl acetate to 2-tertiary butyl amido ethanol 18g, by universal method, add 10%Pd-C1.8g, feed hydrogen, reaction 2h in 40-50 ℃ of normal pressure, filter, filtrate adds 2.4N sulfuric acid 4.7ml under the ice bath cooling, more than the crystallisation by cooling 2h, get the solid 10g of white terbutaline sulphate crystal B.
With 1-(3,5 two benzyloxy phenyl)-2-tertiary butyl amido ethanol 180g joins in the mixed solvent that the aqueous ethyl acetate of 1800ml (water saturation) and tetrahydrofuran (THF) 200ml form, by universal method, add 10%Pd-C 18g, feed hydrogen, reaction 2h in 40-50 ℃ of normal pressure, filter, filtrate adds 2.4N sulfuric acid 47ml under the ice bath cooling, more than the crystallisation by cooling 2h, get the solid 108g of white terbutaline sulphate crystal B.
Embodiment 25
0.5g non-B crystal formation bricalin stirred 24 hours down in 25 ℃ in the aqueous methyl aceto acetate of 10ml (water saturation), filter, with a small amount of ether washing leaching cake, collect filter cake in 50 ℃ of decompressions (but also normal pressure) drying 1 hour, again 80 ℃ of dryings 1 hour, be dried to constant weight at 120 ℃ at last, get terbutaline sulphate crystal B.
Get 1-(3,5-two Bian oxygen base phenyl)-2-n-butylamine-based ethanol 1g, ethyl acetate (water saturation) 10ml, Pd-C0.1g added in the reactor, in 50 ℃ of following hydrogenolysis of normal pressure three hours.Stop heating, remove by filter Pd-C.In the filtrate that collection obtains, add an amount of 50% sulfuric acid, left standstill three hours, get the terbutaline sulphate crystal B crude product.The terbutaline sulphate crystal B crude product that again collection is obtained stirred 12 hours in water saturated ethyl acetate, got the terbutaline sulphate crystal B elaboration.
Obvious the present invention disclosed herein is through taking into full account to realize above-mentioned target, but should be appreciated that one of ordinary skill in the art can propose many improvement and embodiment, therefore, claims cover all these improvement that falls into the spirit and scope of the invention and embodiments.
Claims (10)
1, is used to prepare the method for terbutaline sulphate crystal B, wherein terbutaline sulphate crystal B is characterised in that: use Co-K α radiation, 9.9,12.9,21.5,22.7,25.0,27.6,28.9 ± 0.2 the peak is arranged to spend the X-ray powder diffraction spectrum that 2 θ represent, can be with being positioned at about 8.5,11.3,14.9,15.8,20.0,23.6 ± 0.2 degree 2
The powder X-ray RD pattern of θ or powder X-ray RD pattern as shown in Figure 1 further characterize, and this method steps is as follows:
Select a kind of solvent, 1-(3,5 two benzyloxy phenyl)-2-tertiary butyl amido ethanol is dissolved in wherein, hydrogenolysis is sloughed benzyl, gets the terbutaline free alkali, adds the bricalin that sulfuric acid forms crystal form B again, reclaims the terbutaline sulphate crystal B that forms then;
Or, select a kind of solvent, the bricalin in this solvent has low solubility, and the bricalin of armorphous B is dissolved in wherein, stirs, and terbutaline sulphate crystal B will form, and reclaims the terbutaline sulphate crystal B that forms then;
Described solvent is the solvent orange 2 A that water and esters solvent form, and its proportion of composing is represented with the water content of this esters solvent, is about 0.03% to saturated, and the solvent orange 2 A consumption under agitation forms suspension for guaranteeing bricalin at least;
Described esters solvent is selected from ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, ethyl propionate, propyl propionate, butyl propionate, isopropyl propionate, methyl benzoate, ethyl benzoate, methyl aceto acetate or other can be used as the ester class with following structure that solvent uses:
R wherein
2Expression straight or branched alkane; R
1Represent straight or branched alkane, or contain the alkane derivatives of heteroatoms or heteroatoms replacement, or C
6-C
12Aryl, wherein the hydrogen on the aryl can be replaced by other substituting groups.
2, the preparation method of terbutaline sulphate crystal B according to claim 1 is characterized in that: the ratio of the bricalin of described solvent orange 2 A consumption and 1-(3,5 two benzyloxy phenyl)-2-tertiary butyl amido ethanol or armorphous B is 1ml～1000ml:1g.
3, the preparation method of terbutaline sulphate crystal B according to claim 2 is characterized in that: the ratio of the bricalin of described solvent orange 2 A consumption and 1-(3,5 two benzyloxy phenyl)-2-tertiary butyl amido ethanol or armorphous B is 10ml～20ml:1g.
4, according to the preparation method of one of claim 1-3 described terbutaline sulphate crystal B, it is characterized in that: described solvent orange 2 A is the mixed solvent of water and ethyl acetate, and the ratio of water and ethyl acetate is expressed as 0.03% to saturated with the ethyl acetate water content.
5, method according to claim 4, it is characterized in that: described solvent also useable solvents A and solvent B is formed jointly, described solvent B is by the organic solvent alkanes, ester or lipid, aromatic hydrocarbons, ethers, alcohols, one or more solvents in halogenated hydrocarbon and DMF, DMSO or other organic solvents are formed with arbitrary proportion; The ratio of solvent orange 2 A and solvent B is 10:0～1:9, and optimum proportion is 10:0～7:3; The ratio of the bricalin of mixed solvent consumption and 1-(3,5 two benzyloxy phenyl)-2-tertiary butyl amido ethanol or armorphous B is 1ml～1000ml:1g.
6, method according to claim 5 is characterized in that: the ratio of the bricalin of described mixed solvent consumption and 1-(3,5 two benzyloxy phenyl)-2-tertiary butyl amido ethanol or armorphous B is 10ml～20ml:1g.
7, according to the described method of claim 6, it is characterized in that: the alkanes of described organic solvent B is selected from hexane, heptane, hexanaphthene, and sherwood oil or other can be used as the alkane that solvent uses; The ester class is selected from ethyl acetate, propyl acetate, butylacetate, isopropyl acetate, methyl benzoate, ethyl benzoate, methyl aceto acetate or other can be used as ester or the grease that solvent uses; Ketone is selected from acetone, 2-butanone or pimelinketone or other can be used as the ketone that solvent uses; Aromatic hydrocarbons is selected from benzene, toluene or dimethylbenzene or other can be used as the aromatic hydrocarbons that solvent uses, ethers is selected from tetrahydrofuran (THF), ether, isopropyl ether or methyl tertiary butyl ether or other and can be used as the ether that solvent uses, and alcohols is selected from methyl alcohol, ethanol Virahol, various butanols, various amylalcohol, various hexanol or other can be used as the alcohol that solvent uses; Halogenated hydrocarbon is selected from methylene dichloride, chloroform or other can be used as the halocarbon that solvent uses.
8, according to the described method of claim 7, it is characterized in that: described solvent B is one or more in acetone, benzene, tetrahydrofuran (THF), ether, ethanol, methylene dichloride or the chloroform.
9, method according to claim 1 is characterized in that: the temperature range of described stirring is 0 ℃ and arrives reflux temperature; Churning time is 10 minutes-100 hours.
10, method according to claim 1 is characterized in that terbutaline sulphate crystal B that described recovery forms adopts a kind of in following three kinds of methods:
A. remove by filter solvent, solid is through decompression or normal pressure heat drying, to obtain terbutaline sulphate crystal B then;
B. under reduced pressure remove and desolvate, solid is through decompression or normal pressure heat drying, to obtain terbutaline sulphate crystal B then;
C. fling to solvent under nitrogen gas stream effect and heating, solid is through decompression or normal pressure heat drying, to obtain terbutaline sulphate crystal B then.
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| WO2021178259A1 (en) * | 2020-03-02 | 2021-09-10 | Wen Tan | A crystalline form (r)-terbutaline hydrochloride |
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