Summary of the invention
The purpose of this invention is to provide the medical compounds, particularly S-(carboxymethyl) of a kind of S-(carboxymethyl)-halfcystine-Cys ammonium salt one water crystallization.
Another object of the present invention provides the preparation method of the preparation method, particularly S-(carboxymethyl) of the medical compounds of a kind of S-(carboxymethyl)-halfcystine-Cys ammonium salt one water crystallization.
A further object of the present invention provides the composition of the medical compounds that comprises S-(carboxymethyl)-halfcystine, particularly comprises the pharmaceutical composition of S-(carboxymethyl)-Cys ammonium salt one water crystallization.
Of the present inventionly advance the medical compounds that a purpose provides S-(carboxymethyl)-halfcystine, S-(carboxymethyl)-Cys ammonium salt one water crystallization particularly, application in the preparation expelling phlegm drugs, and the application in the medicament for treating respiratory system things such as preparation prevention and treatment chronic obstructive pulmonary.
The objective of the invention is to realize by following concrete technical scheme:
The medical compounds of a kind of S-(carboxymethyl)-halfcystine, shown in general formula (I):
Wherein:
R be pharmaceutically acceptable can with the basic cpd of S-(carboxymethyl)-halfcystine salify, x is 1~2 integer, y is 1~5 integer.
General formula of the present invention (I) medical compounds, wherein R can be ammonia or arginine.
General formula of the present invention (I) medical compounds, wherein R does not comprise Methionin.
Compound of the present invention is selected from S-(carboxymethyl)-halfcystine ammonium salt monohydrate, and its structural formula is suc as formula (II).
Its levoisomer is S-(carboxymethyl)-Cys ammonium salt one water crystallization compound, and its structural formula is suc as formula (III).
The present invention further also provides a kind of S-(the carboxymethyl)-medical compounds of halfcystine and the preparation method of isomer thereof, and the method is with S-(carboxymethyl)-halfcystine dissolving or is suspended in the suitable solvent system that preferred solvent is water; Add basic cpd R, fully reaction make solid molten clear after, in reaction solution, add the crystallization solvent, separation, the medical compounds crystallization that gets S-(carboxymethyl)-halfcystine.
" the crystallization solvent " mentioned in the aforesaid method can be regarded as and this reaction product sl. sol. solvent at the most, according to the technical field under the method, dilution crystallization method (or solvent crystallization) is that solute is dissolved in water or other organic solvents, then add certain solvent in the xln solubleness of solute in former solvent is reduced, thus the crystallization method that solute is separated out fast.The solvent that adds is known as crystallization solvent or precipitation agent.
The medical compounds of the S-of making of the present invention (carboxymethyl)-halfcystine and the crystallization solvent that isomer crystallizes is separated out thereof are that to contain C be 1~4 alcohol, such as ethanol, Virahol, n-propyl alcohol, propyl carbinol, 2-butanols; Contain C and be 3~6 ketone, such as acetone, methylethylketone, pentanone; Contain C and be 2~4 nitrile, such as acetonitrile, propionitrile; Contain C and be 2~6 ethers, such as dioxan, tetrahydrofuran (THF); Contain C and be 1~5 amides, such as DMF, N,N-dimethylacetamide; Or more than one combination of above-mentioned solvent.
Particularly, the invention provides the preparation method of S-(carboxymethyl)-Cys ammonium salt one water crystallization compound, the method also can be used for the preparation of S-(carboxymethyl)-Cys ammonium salt one water crystallization isomeric compound, and the method is as follows:
With S-(carboxymethyl)-Cys dissolving or suspend in water, under 20~60 ℃, add an amount of ammoniacal liquor, stirring is fully reacted it, reaction solution molten clear after, add the crystallization solvent, make crystallization, the S-(carboxymethyl) that separation obtains-Cys ammonium salt one water crystallization compound.
Among the above-mentioned preparation method, the detailed process step that is appreciated that is:
(1), with S-(carboxymethyl)-Cys dissolving or be suspended in the suitable solvent system, preferred solvent is water; Under 20~60 ℃, add at least the proper ammonia with S-(carboxymethyl)-Cys equimolar ratio, fully stir S-(carboxymethyl)-Cys and ammoniacal liquor are reacted completely, reaction solution is fully molten clear;
(2), in reaction solution, add the crystallization solvent, namely with reaction product S-(carboxymethyl)-Cys ammonium salt one water crystallization sl. sol. solvent at the most, S-(carboxymethyl)-Cys ammonium salt one water crystallization is progressively reached capacity or hypersaturated state, get final product crystallize out, by continuous adding solvent, control supersaturation process and crystalline growth velocity, it is good that the crystal of separating out is practised, S-(carboxymethyl)-Cys ammonium salt one water crystallization crystal is fully separated out, separate, drying gets S-(carboxymethyl)-Cys ammonium salt one water crystallization.
Above-described Crystallization Process also can join the reaction solution of S-(carboxymethyl)-Cys and ammoniacal liquor in the crystallization solvent (with S-(carboxymethyl)-Cys ammonium salt one water crystallization sl. sol. solvent at the most), after crystal is fully separated out, separate, drying can get S-(carboxymethyl)-Cys one water crystallization equally.
No matter above-described crystallization method is batch crystallization, continuous crystallisation, stirred crystallization, leaves standstill the crystallization operation modes such as crystallization, can implement.
Crystallization solvent described in the preparation method of above S-(carboxymethyl)-Cys ammonium salt one water crystallization compound is that to contain C be 1~4 alcohol, such as ethanol, Virahol, n-propyl alcohol, propyl carbinol, 2-butanols; Contain C and be 3~6 ketone, such as acetone, methylethylketone, pentanone; Contain C and be 2~4 nitrile, such as acetonitrile, propionitrile; Contain C and be 2~6 ethers, such as dioxan, tetrahydrofuran (THF); Contain C and be 1~5 amides, such as DMF, N,N-dimethylacetamide; Or more than one combination of above-mentioned solvent.These solvents or solvent mixture and water soluble and with S-(carboxymethyl)-Cys ammonium salt one water crystallization slightly soluble.
Preferred solvent is ethanol, acetone, Virahol, acetonitrile or their binary, ternary or multicomponent mixture.
The solvability table (25 ℃) of S-(carboxymethyl)-Cys ammonium salt one water crystallization in several solvents:
The solvent title |
Solvability |
Methyl alcohol |
Soluble,very slightly |
Virahol |
Soluble,very slightly |
Dehydrated alcohol |
Soluble,very slightly |
Acetone |
Soluble,very slightly |
Acetonitrile |
Soluble,very slightly |
DMF |
Soluble,very slightly |
S-of the present invention (carboxymethyl)-Cys ammonium salt one water crystallization size-grade distribution is comparatively even, after storing for some time under the normal temperature, proterties is not observed obvious variation, and character is comparatively stable, be difficult for the moisture absorption, the moisture content difference that records after placement for some time is little.
Being used in combination following various analytical procedure analyzes the specific crystal formation sample of S-(carboxymethyl)-Cys ammonium salt monohydrate: X-ray powder diffraction analytical method (hereinafter claiming XRPD), dsc (hereinafter claiming DSC), thermogravimetry (hereinafter claiming TG), fusing point, solid state nmr method, ion chromatography, infrared spectroscopy.Because the data that different instruments and different condition can cause producing can be slightly different, therefore the following numerical value of quoting is not considered as absolute numerical value.
X ray diffracting data is obtained by the D/max-3A X-ray diffractometer, adopts Cu-K α
1The following X-ray powder diffraction pattern (accompanying drawing 14) that radionetric survey is expressed with Bragg angle 2 θ, relative intensity (to express with respect to the percentage ratio of strong ray):
That as above carries depends on used measuring condition, and the intensity at each peak can change to some extent on the XRPD diffractogram, does not therefore use the numeral relative intensity, but uses following intensity definition:
The % relative intensity |
Definition |
25-100 |
VS (very strong) |
10-25 |
S (by force) |
3-10 |
M (medium) |
1-3 |
W (weak) |
8.5 °, 19.7 °, 21.5 °, 23.5 °, 27.5 °, 29.2 ° and 32.5 ° of diffraction angle of the X-ray diffractogram of above-mentioned data acknowledgement S-(carboxymethyl)-Cys ammonium salt monohydrate (2 θ angle ± 0.2 °) locate to have characteristic peak.
Infared spectrum is obtained by FT-IR NICOLET 6700 instruments, and it is the charateristic avsorption band of carboxylate salt that the infared spectrum (Figure 15) of the KBr compressing tablet of S-(carboxymethyl)-Cys ammonium salt monohydrate has following charateristic avsorption band: 1600-1610cm-1,1550-1559cm-1,1400-1410cm-1;-N-H absorption frequency is also in this scope of 1600-1610cm-1,1550-1559cm-1, and is overlapping to some extent with the absorption of carboxylate salt; 1470-1480cm-1 is-the C-H-absorption peak.
The infared spectrum of the KBr compressing tablet of above-mentioned data acknowledgement S-(carboxymethyl)-Cys ammonium salt one water crystallization medical compounds has 1600-1610cm-1,1550-1559cm-1,1470-1480cm-1,1400-1410cm-1 charateristic avsorption band.
Analyze with the Optimelt melting point apparatus, between 115-119 ℃, observe S-(carboxymethyl)-Cys ammonium salt monohydrate and melt.
The TG data are obtained by German NETZSCH company's T G209 instrument, under air atmosphere, are warming up to 350 ℃ with the speed of 10 ℃/min, the record thermogravimetric curve.As shown in figure 10, the TG differential thermogram has shown at 55 ℃ of left and right sides compounds and has begun weightlessness that 95-135 ℃ of scope internal loss is about 8~9%, and be consistent with the theoretical content 8.4% of water in S-(carboxymethyl)-Cys ammonium salt monohydrate.
The DSC the data Germany NETZSCH DSC204 of company instrument is analyzed, and is warming up to 165 ℃ with 10 ℃/min speed under nitrogen atmosphere, the record heating curve.Shown in the DSC figure (Fig. 9), the peak value (heat-absorbing action is about 55 ℃ of beginnings) about about 95 ℃ of heat absorption has for the second time heat-absorbing action about 117 ℃ for the first time.With reference to measured fusing point and TG data, showing in the process of heating S-(carboxymethyl)-Cys ammonium salt monohydrate has the dehydration phenomenon about 95 ℃, is the fusing heat absorption about 117 ℃.TG and DSC data results show that S-(carboxymethyl)-Cys ammonium salt monohydrate desolvation point is in 55-115 ℃ of scope.
Adopt Bruker AVANCE AV400 million superconduction pulse fourier transform nmr spectrometers to carry out structural characterization (Figure 11 and Figure 12), S-(carboxymethyl)-Cys ammonium salt monohydrate has following principal character:
1H-NMR (D
2O, 400MHz) δ: 3.04 (m, 1H, CH
2), 3.16 (m, 1H, CH
2), 3.30 (m, 2H, CH
2), 3.91 (m, 1H, CH);
13C-NMR (D
2O, 400MHz) δ: 178.07 (C-5), 173.25 (C-1), 54.16 (C-2), 37.52 (C-4), 33.91 (C-3).
The chromatography of ions result (Figure 13) who adopts Dionex DX-600 instrumental analysis to obtain shows NH
4 +% content is 8.35~8.50%, NH in this and S-(the carboxymethyl)-Cys ammonium salt monohydrate
4 +Theoretical content is consistent.
After the present invention uses S-(carboxymethyl)-Cys and pharmaceutically acceptable suitable inorganic base salts or organic bases salify, be hydrolyzed in vivo after being absorbed by the body and generate S-(carboxymethyl)-Cys, when keeping S-(carboxymethyl)-Cys drug effect, can reduce the acidity of S-(carboxymethyl)-Cys to gastral stimulation, reduce its side effect.
Preferred version S-of the present invention (carboxymethyl)-Cys ammonium salt one water crystallization compound is the solubility double salt that utilizes the alkalescence of the acidity of its carboxyl and ammoniacal liquor to form.S-(carboxymethyl)-Cys ammonium salt one water crystallization is very easily water-soluble, can under the hydrochloric acid in gastric juice effect, be hydrolyzed into S-(carboxymethyl)-Cys and ammonium chloride after being absorbed by the body, can not only reduce S-(carboxymethyl)-Cys to GI stimulation, unnecessary hydrochloric acid in gastric juice also can neutralize.After S-(carboxymethyl)-Cys ammonium salt one water crystallization hydrolysis, S-(carboxymethyl)-Cys continues to bring into play its pharmacological action in vivo, simultaneously, the ammonium chloride that hydrolysis generates has chemical irritation to mucous membrane, energy reflectivity ground increases amount of expectoration, makes sputum be easy to discharge, and is conducive to be difficult for a small amount of removing of gluing phlegm of expectoration, to the synergism of having reduced phlegm of S-(carboxymethyl)-Cys, more be conducive to improve curative effect.The security of S-(carboxymethyl)-Cys ammonium salt is good, and side effect is little, can be used for the Disease long-term takings such as chronic obstructive pulmonary disease.
The present invention also provides a kind of pharmaceutical composition, comprise take S-(carboxymethyl)-halfcystine medical compounds as effective constituent and must use carrier, more specifically, be pharmaceutical composition take S-(carboxymethyl)-Cys ammonium salt one water medical compounds as effective constituent and pharmaceutically acceptable carrier.
The present invention also provides the medical compounds of such S-(carboxymethyl)-halfcystine, the particularly application of S-(carboxymethyl)-Cys ammonium salt one water crystallization compound in the preparation expelling phlegm drugs, and the application in preparation prevention and treatment chronic obstructive pulmonary medicament for treating respiratory system thing.
The effect of drugs experiment
1. experimental technique
1.1 the preparation of rat copd model
90 rats are divided into 6 groups at random, are respectively normal group, model group, positive group, high, normal, basic dosetest group, 15 every group.Adopt the method that splashes into induced by lipopolysaccharide (LPS) in the at present internal and international upper fumigation gas-adding pipe of generally using to set up the rat copd model.Cycle is 3 months (90 days).Concrete grammar: at the 1st, 15,29,43,57,71,85 day of test, use the etherization rat, pull out the root of the tongue of rat, splash into LPS (200ug/200ul) with elbow gavage syringe needle through tracheae.Normal group splashes into the physiological saline of equivalent, not fumigation with identical method.All the other 5 groups of rats place homemade fumigation storehouse fumigation every day.The external negative pressure pump of fumigation storehouse one side, the top is connected to the socket of cigarette.Connect the electric current of negative pressure pump, igniting cigarette can enter the fume extraction of cigarette in the fumigation storehouse.Dead because of anoxic in order to prevent animal, light 12 cigarettes at every turn, open Cang Gai behind the fumigation 20min and renew bright air.1h/3 times/day, add with elbow gavage syringe needle and splash into LPS (200ug/200ul) through tracheae.
1.2 drug intervention
Experiment totally 90 days, began to carry out drug intervention on the 15th day from experiment, positive group perfusion S-carboxymethylcysteine, high test group perfusion various dose trial drug (being S-carboxymethyl Cys ammonium salt one water crystallization) in hanging down, the physiological saline of model group and normal rats perfusion equivalent.
1.3 index determining
The second day eye socket is got blood after experiment finishes, separation of serum and leave and take lung tissue, get right upper lung and carry out the pathologic detection, after remaining lung carries out lung tissue homogenate, measure oxidative and anti-oxidative index lipid peroxide (LPO), mda (MDA), reduced glutathion (GSH) content and superoxide-dismutase (SOD) activity, the concentration of inflammatory mediator TNF-α, IL-8, IL-6.Carry out without the lung function tests of creating and have wound.
2. experimental result
2.1 animal performance in the experimentation
Normal rats is vivaciously active, the hair polishing, color and luster is arranged; Model and administration treated animal integrality are not good enough, cough, One's spirits are drooping, tired sleeping successively occurs, be slow in action, the withered jaundice of hair, mixed and disorderly, the sings and symptoms such as come off.
2.2 pathological change
Normal rats tunica mucosa bronchiorum epithelial structure is relatively complete, the cilium marshalling, and rare obviously inflammatory cell infiltration under the mucous membrane, the alveolar structure continuous whole, alveolar space has no obvious expansion and inflammatory exudation (seeing attached Fig. 1 and 2).The narrow distortion of model group rat bronchiole even obturation; Cilium adhesion, lodging have obviously to come off, and the air flue mucosal degeneration is downright bad, and epithelial cell, the remarkable hyperplasia of goblet cell have massive inflammatory cells infiltrated under the film and around the bronchiole, take lymphocyte as main; The airway smooth muscle hyperplasia, lung arteriole unstriated muscle thickens; Pulmonary emphysema are obvious, and visible bulla forms (seeing accompanying drawing 3 and 4).Inflammatory cell infiltration, air flue mucosal degeneration degree of necrosis and lung arteriole proliferation of smooth muscle thickness are all light than model group under each medication group bronchial mucosa.The wherein narrow distortion of positive group rat bronchiole, cilium adhesion, lodging, the attenuation of part alveolus wall, alveolar space enlarges, inflammatory cell infiltration under the bronchial mucosa (seeing accompanying drawing 5 and 6).The narrow distortion of trial drug group rat bronchiole, mucous membrane lodges, comes off, and the air flue mucosal degeneration has lymphocytic infiltration under downright bad epithelial cell, the mucous membrane and around the bronchiole; The interstitial lung inflammatory cell infiltration.(seeing accompanying drawing 7 and 8).
2.3 the mensuration of Raw air way resistance
Under the identical operating pressure, compare with normal group, the model group rat is without wound and have the wound Raw air way resistance all significantly to increase (P<0.01), shows the animal model success.Compare with model group, give trial drug treatment after, Raw air way resistance obviously reduces, and is a certain amount of effect relationship.Test-results sees Table 1.
Table 1 is on the impact of Raw air way resistance
Annotate: compare * * P<0.01 with model group
2.4 the mensuration of inflammation index
Compare with normal group, TNF-α, IL-8, IL-6 content all significantly increase (P<0.01) in model group induced lung and the serum, show the animal model success.Compare with model group, give simultaneously the trial drug treatment, TNF-α, IL-8, IL-6 content, and be a certain amount of effect relationship.Test-results sees Table 2.
Table 2 on the impact of inflammation index (
Pg/mL)
Annotate: compare * P<0.05, * * P<0.01 with model group
2.5 the mensuration of oxidation and Antioxidant Indexes
Compare with normal group, oxidation index LPO, MDA content all significantly increase (P<0.01) in model group induced lung and the serum, and Antioxidant Indexes GSH and SOD content all significantly reduce cost (P<0.01), show the animal model success.Compare with model group, give simultaneously the trial drug treatment, LPO, MDA content all significantly reduce in lung and the serum, and GSH and SOD content all significantly raise, and are a certain amount of effect relationship.Test-results sees Table 3 and table 4.
Table 3 is on the impact of oxidation index
Annotate: compare * P<0.05, * * P<0.01 with model group
Table 4 is on the impact of Antioxidant Indexes
Annotate: compare * P<0.05, * * P<0.01 with model group
3. experiment conclusion
The key character of COPD is the persistence inflammatory disorders of whole air flue and pulmonary parenchyma, and oxidation antioxidation is unbalance, and vivo oxidation stress strengthen.Preliminary drug effect result shows, the COPD rat model gives trial drug simultaneously in modeling in the time of the 15th day can significantly reduce Raw air way resistance under the uniform pressure, reduce the generation of oxide compound, increase the level of antioxidant, oxidation-antioxidation is tended to balance, alleviate oxide compound, inflammatory mediator etc. to the damage of lung, this is consistent with the result that pathology section examination arrives.
Beneficial effect
Gained S-of the present invention (carboxymethyl)-Cys medical compounds, particularly S-(carboxymethyl)-Cys ammonium salt one water crystallization is a kind of well-crystallized that distributes than uniform particle size, stable in properties, be difficult for the moisture absorption, be easy to preserve and make the relative medicine preparation.The easy easy control of preparation method of this S-(carboxymethyl)-Cys medical compounds, particularly S-(carboxymethyl)-Cys ammonium salt one water crystallization, yield is high, and with short production cycle, environmental pollution is little, is conducive to large-scale production and application.Preliminary drug effect result shows that compound of the present invention can significantly reduce COPD rat model Raw air way resistance, reduces the generation of oxide compound, increases the level of antioxidant, alleviates oxide compound, inflammatory mediator etc. to the damage of lung.
Embodiment
Below with specific examples technical scheme of the present invention is described, protection scope of the present invention is not limited to this.
The preparation of S-(carboxymethyl)-Cys ammonium salt one water crystallization:
Embodiment 1
Under the room temperature, in the there-necked flask of whipping appts is housed, add 50g S-(carboxymethyl)-Cys, 40ml distilled water, add 25ml 25% ammoniacal liquor in the suspension liquid that obtains, rapid stirring gets settled solution again, to wherein dripping 600ml ethanol, rate of addition is slightly fast during beginning, the rate of addition that when the adularescent crystal is separated out, slows down, after ethanol dropwises, 25 ℃ of lower growing the grains, suction filtration, a small amount of washing with alcohol filter cake is drained drying, get white S-(carboxymethyl)-Cys ammonium salt one water crystallization 56.5g, yield about 94.5%.
Embodiment 2
Under the room temperature, in the there-necked flask of whipping appts is housed, add 25g S-(carboxymethyl)-Cys, 20ml distilled water, add 14ml 25% ammoniacal liquor in the suspension liquid that obtains, rapid stirring gets settled solution again, to wherein dripping the 400ml Virahol, rate of addition is slightly fast during beginning, the rate of addition that when the adularescent crystal is separated out, slows down, after Virahol dropwises, 25 ℃ of lower growing the grains, suction filtration, a small amount of washed with isopropyl alcohol filter cake is drained drying, get white S-(carboxymethyl)-Cys ammonium salt one water crystallization 28.5g, yield about 95.4%.
Embodiment 3
Under the room temperature, in the there-necked flask of whipping appts is housed, add 50g S-(carboxymethyl)-Cys, 40ml distilled water, add 30ml 25% ammoniacal liquor in the suspension liquid that obtains, rapid stirring gets settled solution again, to wherein dripping 600ml acetone, rate of addition is slightly fast during beginning, the rate of addition that when the adularescent crystal is separated out, slows down, after acetone dropwises, 25 ℃ of lower growing the grains, suction filtration, a small amount of washing with acetone filter cake is drained drying, get white S-(carboxymethyl)-Cys ammonium salt one water crystallization 57.4g, yield about 96.0%.
Embodiment 4
Under the room temperature, in the beaker of whipping appts is housed, add 25g S-(carboxymethyl)-Cys, 20ml distilled water adds 14ml 25% ammoniacal liquor again in the suspension liquid that obtains, and rapid stirring gets settled solution, and is for subsequent use; In the there-necked flask that whipping appts is housed, add 400ml acetone, heating in water bath to 50 ℃ stirs and lower settled solution in the beaker slowly is added dropwise in the acetone, and the adularescent crystal is separated out, dropwise the recession water-bath, 25 ℃ of lower growing the grains, suction filtration, a small amount of washing with acetone filter cake, drain, drying gets white S-(carboxymethyl)-Cys ammonium salt one water crystallization 28.2g, yield about 94.4%.
Embodiment 5
Under the room temperature, in the there-necked flask of whipping appts is housed, add 50g S-(carboxymethyl)-Cys, 40ml distilled water, add 30ml 25% ammoniacal liquor in the suspension liquid that obtains, rapid stirring gets settled solution again, to wherein dripping the 600ml acetonitrile, rate of addition is slightly fast during beginning, the rate of addition that when the adularescent crystal is separated out, slows down, after acetonitrile dropwises, 25 ℃ of lower growing the grains, suction filtration, a small amount of acetonitrile washing leaching cake is drained drying, get white S-(carboxymethyl)-Cys ammonium salt one water crystallization 58.5g, yield about 97.0%.
Embodiment 6
Under the room temperature, in the there-necked flask of whipping appts is housed, add 40g S-(carboxymethyl)-Cys, 30ml distilled water, add 24ml 25% ammoniacal liquor in the suspension liquid that obtains, rapid stirring gets settled solution again, to wherein dripping the 500ml tetrahydrofuran (THF), rate of addition is slightly fast during beginning, the rate of addition that when the adularescent crystal is separated out, slows down, after tetrahydrofuran (THF) dropwises, 25 ℃ of lower growing the grains, suction filtration, a small amount of washing with acetone filter cake is drained drying, get white S-(carboxymethyl)-Cys ammonium salt one water crystallization 26.5g, yield about 55.4%.
Embodiment 7
Under the room temperature, in the there-necked flask of whipping appts is housed, add 40g S-(carboxymethyl)-Cys, 30ml distilled water, add 24ml 25% ammoniacal liquor in the suspension liquid that obtains, rapid stirring gets settled solution again, to wherein dripping 500ml methyl alcohol, rate of addition is slightly fast during beginning, the rate of addition that when the adularescent crystal is separated out, slows down, after methyl alcohol dropwises, 35 ℃ of lower growing the grains, suction filtration, a small amount of methanol wash filter cake is drained drying, get white S-(carboxymethyl)-Cys ammonium salt one water crystallization 44.95g, yield about 94.0%.
Embodiment 8
Under the room temperature, in the there-necked flask of whipping appts is housed, add 40g S-(carboxymethyl)-Cys, 30ml distilled water adds 24ml 25% ammoniacal liquor again in the suspension liquid that obtains, rapid stirring gets settled solution, to wherein dripping the 500ml DMF, rate of addition is slightly fast during beginning, rate of addition slows down when the adularescent crystal is separated out, after DMF dropwises, 45 ℃ of lower growing the grains, suction filtration, a small amount of washing with acetone filter cake is drained drying, get white S-(carboxymethyl)-Cys ammonium salt one water crystallization 46.8g, yield about 98.0%.
Embodiment 9
The sylvite of general formula I (in Carbocisteine) 1 mass parts
Chlorine is pricked aniline 0.1 mass parts
Water (add an amount of phosphoric acid salt and regulate pH to 6) 98.9 mass parts
With above-mentioned prescription drug and auxiliary materials and mixing, embedding can obtain sprays in the quantitative valve container.
Embodiment 10
Compound III (in Carbocisteine) 1 mass parts
Bromine is pricked aniline 0.1 mass parts
Water (add an amount of borate and regulate pH to 7) 98.9 mass parts
With above-mentioned prescription drug and auxiliary materials and mixing, embedding can obtain sprays in the quantitative valve container.
Embodiment 11
Compound III (in Carbocisteine) 1.5 mass parts
Bromine is pricked aniline 0.1 mass parts
Water (add an amount of borate and regulate pH to 7) 98.4 mass parts
With above-mentioned prescription drug and auxiliary materials and mixing, embedding can obtain sprays in the quantitative valve container.