CN104844512B - A kind of preparation method of green card color woods hydrochloride semi-hydrate crystal formation - Google Patents
A kind of preparation method of green card color woods hydrochloride semi-hydrate crystal formation Download PDFInfo
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- CN104844512B CN104844512B CN201510247144.1A CN201510247144A CN104844512B CN 104844512 B CN104844512 B CN 104844512B CN 201510247144 A CN201510247144 A CN 201510247144A CN 104844512 B CN104844512 B CN 104844512B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
Abstract
The invention belongs to a kind of preparation method of the green card color woods hydrochloride semi-hydrate crystal formation in compound crystal form preparation field, methods described comprises the steps：（1）After green card color woods hydrochloride is dissolved completely in the first organic solvent, water, stirring, concentration is added to remove solvent, obtain grease；（2）The second organic solvent is added in the grease, is stirred, is obtained green card color woods hydrochloride semi-hydrate crystal formation.The method need not control hydrogen chloride gas intake and need not realize turning brilliant process by heating, and have the advantages that easily controllable, gentle reaction condition, high income and products obtained therefrom quality are good.
Description
Technical field
The invention belongs to a kind of preparation of the green card color woods hydrochloride semi-hydrate crystal formation in compound crystal form preparation field
Method.
Background technology
With expanding economy and the improvement of people's living standards, incidence of obesity is in rapid increase trend, and increasingly
Paid close attention to by people.In the U.S., the adult and about 25% children more than 50% is overweight or fat, and only nineteen ninety-five is used for
The fat expense for the treatment of has just exceeded 70,000,000,000 dollars.2002 " Chinese residents nutrition and health survey " shows, China
Rate that adult is overweight and obesity rates are respectively 22.8% and 7.1%, estimate China's obesity number about 60,000,000 at present, overweight number
Then more than 200,000,000.Compared with investigation in 1992, overweight rate of being grown up rises 39%, and obesity rates rise 97%.Wherein big city adult
Overweight rate and obesity rates even as high as 30.0% and 12.3%, children obesity rate is up to 8.1%.Fat and angiocardiopathy, II types
Various diseases such as diabetes, hypertension, dyslipidemia, hyperuricemia, some tumours and sleep disordered breathing are closely related, grind
Study carefully display obese degree also closely related with case fatality rate.
Green card color woods（LORCASERIN）It is the medicine for acting on central nervous system impression appetite, in 2005 by the U.S.
Arena Pharm Inc (Arena Pharmaceuticals Inc) develops, on June 27th, 2012 on the U.S. is granted
City, trade name Belviq, subsequently in the Peurto Rican granted listing of North America.Its specific target spot is 5-HT2c, for control
Appetite play the role of it is very strong, and for 5-HT2AOr 5-HT2BAcceptor is not then acted on, the two acceptors respectively with cardiovascular disease
Disease to cause hallucinations it is related.
Patent publication No. has three kinds of crystal formations for green card color woods hydrochloride is reported in the patent of CN102321023A, respectively
For crystal formation I, crystal formation II and crystal formation III.Crystal formation I and crystal formation II are anhydrous, moisture absorption forms, and both forms are all easily in exposure
More stable crystal formation III is converted into after moisture.The medicinal listing crystal formation of the product is green card color woods hydrochloride Form III, i.e.,
Green card color woods hydrochloride semi-hydrate crystal formation, its structural formula are as follows：
The preparation method of green card color woods crystal formation III of the patent publication No. to report in CN101466684A is by green card color woods
Free alkali is dissolved in ethyl acetate, after adding quantitative purified water to stir, quantitative chlorine is slowly introducing at 0～5 DEG C
Change hydrogen, gas is passed through after finishing, be further continued for stirring 2 hours, filter, washing, dry target product.In the method, chlorine
The intake for changing hydrogen is wayward.If hydrogen chloride is passed through excess, target product is most to be dissolved in solvent again, causes
The low shortcoming of yield, this is that pharmaceutical producing enterprise is not intended to see.
The preparation method of green card color woods crystal formation III of the patent publication No. to report in CN102321023A is by green card color woods
Hydrochloride is dissolved in isopropanol in 60 DEG C, adds water and hexamethylene, after stirring, 2 hours slow coolings of Jing to 20～
25 DEG C, continue to be cooled to 0～5 DEG C and stir 3 hours, filter, washing, be dried after target product.The preparation method is due to temperature
It is higher, cause target product part that configuration conversion occurs, therefore cause optical purity of products to reduce, so as to have impact on the matter of finished product
Amount.Therefore, it is urgently to be resolved hurrily at present to develop a kind of new method for preparing green card color woods hydrochloride semi-hydrate crystal formation
New problem.
The content of the invention
It is an object of the invention to provide a kind of preparation method of green card color woods hydrochloride semi-hydrate crystal formation, the method without
Hydrogen chloride gas intake need to be controlled and need not realize turning a brilliant process by heating, with reaction condition it is easily controllable, gentle,
The advantages of high income and good products obtained therefrom quality.
For achieving the above object, the present invention is adopted the following technical scheme that：A kind of green card color woods hydrochloride semi-hydrate crystal formation
Preparation method, methods described comprises the steps：
（1）After green card color woods hydrochloride is dissolved completely in the first organic solvent, water is added, stirring, concentration remove molten
Agent, obtains grease；
（2）The second organic solvent is added in the grease, is stirred, obtain green card color woods hydrochloride semi-hydrate brilliant
Type；
The one kind of first organic solvent in absolute methanol, absolute ethyl alcohol, isopropanol, dichloromethane, preferably two
Chloromethanes；The one kind of second organic solvent in toluene, n-hexane, hexamethylene, petroleum ether, ethyl acetate, acetone, it is excellent
Select ethyl acetate；
The preparation method of the green card color woods hydrochloride is that green card color woods free alkali is dissolved completely in the 3rd organic solvent
Afterwards, hydrogen chloride gas are passed through in reactant liquor until after saturation, removing the 3rd organic solvent and obtaining green card color woods hydrochloride, it is described
The one kind of 3rd organic solvent in absolute methanol, absolute ethyl alcohol, isopropanol, dichloromethane, acetone, ether, preferred dichloro
Methane；Described green card color woods hydrochloride semi-hydrate crystal formation, in the X-ray powder diffraction collection represented with 2 θ angles, bag
Include 10.3,12.7,13.7,14.9,15.5,15.8,16.7,18.5,18.9,19.2,20.0,20.5,21.4,22.8,
23.2nd, 23.4,24.0,24.8,25.4,25.7,26.6,26.9,27.5,28.2,29.0 have main diffraction maximum, the 2 θ angles
Error range ± 0.2；Described green card color woods hydrochloride semi-hydrate crystal formation has X-ray powder substantially as shown in Figure 1
Diffracting spectrum；Described green card color woods hydrochloride semi-hydrate crystal formation in Differential Scanning Calorimetry, at about 94 DEG C and 202 DEG C
Place has endothermic peak at two respectively, wherein 94 DEG C are dehydration peak, 202 DEG C is sample melted peak；Described green card color woods hydrochloride
Weight is 1 with the volume ratio of the first organic solvent:5～1:20, the weight of described green card color woods hydrochloride is organic with second molten
The volume ratio of agent is 1:10～1:30, the unit of the quality for gram, the unit of the volume is milliliter, described green card color woods
Hydrochloride is 1 with the mol ratio of water:0.5～1:0.6；The quality of the green card color woods free alkali and the volume of the 3rd organic solvent
Than for 1:5～1:20, the unit of the quality for gram, the unit of the volume is milliliter；The 3rd described organic solvent is aqueous
Weight content be less than 0.5%, preferably aqueous weight content is less than 0.2%；It is described that green card color woods free alkali is dissolved completely in
After 3rd organic solvent, hydrogen chloride gas are passed through in reactant liquor until the temperature of the process of saturation is 0～5 DEG C；In step（1）
In, the temperature being completely dissolved is 25～30 DEG C, and the time being stirred after adding water is 1-3 hours；The side of the concentration
Formula is vacuum distillation, and the temperature of the vacuum distillation is 25-30 DEG C；The aqueous weight content of first organic solvent is less than
0.5%, preferably aqueous weight content is less than 0.2%；In step（2）In, the temperature of the grease is 0～5 DEG C, to the oil
The mode of the second organic solvent is added in shape thing to be added dropwise, the temperature during stirring is 0～5 DEG C, the time of the stirring is
1-3 hours, after the stirring also include filter, washing, be dried step, the washing adopt for the second organic solvent；
Described hydrogen chloride gas are dry hydrogen chloride gas, and the mode for being passed through hydrogen chloride gas is to be slowly introducing, described to remove
Go the mode of the 3rd organic solvent to remove under reduced pressure, the temperature for removing under reduced pressure is 25-30 DEG C.
The present invention is characterized by the preparation method of green card color woods hydrochloride semi-hydrate crystal formation.Its pharmacy principle is：（1）
After green card color woods hydrochloride is dissolved completely in the first organic solvent at 25～30 DEG C, water is added, is stirred at 25～30 DEG C
Mix 1～3 hour, make green card color woods hydrochloride that transformation of crystal to occur, so as to obtain green card color woods hydrochloride semi-hydrate crystal formation, it
Vacuum distillation concentration is carried out at 25 DEG C and removes solvent, obtain grease.Is added at 0～5 DEG C in the grease
Two organic solvents, stirring, make green card color woods hydrochloride semi-hydrate separate out from solvent, obtain with crystalloid green card color woods
Hydrochloride semi-hydrate crystal formation, the one kind of the first organic solvent in absolute methanol, absolute ethyl alcohol, isopropanol, dichloromethane,
It is preferred that dichloromethane, the one kind of the second organic solvent in toluene, n-hexane, hexamethylene, petroleum ether, ethyl acetate, acetone,
Ethyl acetate, this kind of rotating crystal method are carried out at 25～30 DEG C, and reaction condition is gentle, are not susceptible to configuration transformation, gained
Optical purity of products it is high.（2）The preparation method of the green card color woods hydrochloride is to be dissolved completely in green card color woods free alkali
After 3rd organic solvent, hydrogen chloride gas are slowly introducing in reactant liquor in 0～5 DEG C until after saturation, reducing pressure at 25-30 DEG C
The hydrogen chloride gas that the 3rd organic solvent and excess is distilled off obtain green card color woods hydrochloride, and the 3rd organic solvent is selected from anhydrous
One kind in methyl alcohol, absolute ethyl alcohol, isopropanol, dichloromethane, acetone, ether, preferred dichloromethane.The chlorination that the process is passed through
Hydrogen is dry hydrogen chloride gas, and the process being passed through slowly and should control temperature in the range of 0～5 DEG C, to avoid temperature
Raise and produce new impurity, even if hydrogen chloride gas are passed through excessively does not interfere with product yield yet.（3）React each step using have
Machine solvent is single organic solvent, it is to avoid the use of mixed solvent, solvent can be with recoveries, thus preparation cost is low, green
Colour circle is protected.
A kind of preparation method of green card color woods hydrochloride semi-hydrate crystal formation compared with prior art, with the preparation method
Simply, reaction condition is gentle, solvent source is wide, post processing is simple, recycled solvent, low cost, obtained product optics
The advantages of purity height and few relevant material, it is suitable for industrialized production, will be widely used in chemical pharmacy field.
Description of the drawings
Below in conjunction with the accompanying drawings and embodiment the present invention is described in detail.
Fig. 1 is the X-ray powder diffraction pattern of green card color woods hydrochloride semi-hydrate crystal formation in embodiment one.
Fig. 2 is the infrared absorpting light spectra of green card color woods hydrochloride semi-hydrate crystal formation in embodiment one.
Fig. 3 is the differential scanning calorimetry differential thermogram of green card color woods hydrochloride semi-hydrate crystal formation in embodiment one
Spectrum.
Specific embodiment
With reference to embodiment, the present invention is described further, and embodiment contributes to more fully understanding the present invention, but
The present invention is not limited only to following embodiments.
Embodiment one
（a）The preparation of green card color woods hydrochloride
At 0～5 DEG C, to 10.0 g（0.05mol）100 mL dichloromethane are added in green card color woods free alkali（Moisture
0.1%）, stir to clarify after making to be completely dissolved, be slowly introducing in reactant liquor dry hydrogen chloride gas until saturation after, 25
Remove dichloromethane at DEG C under reduced pressure and obtain 11.5 g of off-white powder shape green card color woods HCl, solid, yield 97.0%.
（b）The preparation of green card color woods hydrochloride semi-hydrate crystal formation
（1）At 25～30 DEG C, to 11.5 g（0.05mol）115 mL dichloromethane are added in green card color woods hydrochloride
（Moisture 0.1%）, stir to clarify after making to be completely dissolved, add 0.45 g（0.025mol）Distilled water, after stirring 1.5 hours, 25
Vacuum distillation at DEG C carries out concentration and removes solvent, obtains sticky grease.
（2）Sticky grease is cooled to into 0～5 DEG C, 173mL ethyl acetate is added dropwise in grease under stirring, 0～5
Continue stirring 2 hours at DEG C.A large amount of White crystalline solids are separated out, suction filtration is washed with 0～5 DEG C of ethyl acetate of 20ml, 30 DEG C
It is dried to constant weight in vacuum drying chamber, obtains white crystalline green card color woods hydrochloride semi-hydrate crystal formation solid 11.3g, yield
95.0%, purity 99.5%.
1H-NMR (instruments：BRUKER AV-600 type NMR instrument, solvent：D2O) δ:1.669～1.681 (d, 3H),
3.281～3.298 (m, 1H), 3.358～3.3.394 (m, 2H), 3.450～3.493 (m, 1H), 3.646～3.679 (m,
2H), 3.695 (m, 1H), 7.454～7.468 (d, 1H), 7.497～7.514 (d, d, 1H), 7.584～7.587 (d, 1H).
13C-NMR (instruments：BRUKER AV-600 type NMR instrument, solvent：D2O) δ:19.515,33.615,37.337,
47.974,53.540,129.218,129.821,134.183,135.411,139.550,147.119;ESI-MS m/z:196
[M-HCl+H]+。
By differential scanning calorimetry（DSC）Sample crystal formation is characterized, in DSC curve, at about 94 DEG C and 202 DEG C
There is endothermic peak at two respectively, wherein 94 DEG C are dehydration peak, 202 DEG C is sample melted peak, sees accompanying drawing 3.
The crystal formation have comprising for about 10.3 ° of 2 θ values, 12.7 °, 13.7 °, 14.9 °, 15.5 °, 15.8 °, 16.7 °,
18.5°、18.9°、19.2°、20.0°、20.5°、21.4°、22.8°、23.2°、23.4°、24.0°、24.8°、25.4°、
25.7 °, 26.6 °, 26.9 °, 27.5 °, 28.2 °, the X-ray powder diffraction pattern at peak at 29.0 °, are shown in accompanying drawing 1.
Embodiment two
（a）The preparation of green card color woods hydrochloride
At 0～5 DEG C, to 100.0g（0.51mol）1500mL isopropanols are added in green card color woods free alkali（Moisture
0.2%）, stir to clarify after making to be completely dissolved, be slowly introducing in reactant liquor dry hydrogen chloride gas until saturation after, 30
Remove isopropanol at DEG C under reduced pressure and obtain off-white powder shape green card color woods HCl, solid 113.0g, yield 95.0%.
（b）The preparation of green card color woods hydrochloride semi-hydrate crystal formation
（1）At 25～30 DEG C, to 113.0g（0.487mol）1700mL isopropanols are added in green card color woods hydrochloride（Water
Divide 0.2%）, stir to clarify after making to be completely dissolved, add 5.0g（0.278mol）Distilled water, after stirring 1.5 hours, at 30 DEG C
Vacuum distillation carries out concentration and removes solvent, obtains sticky grease.
（2）Sticky grease is cooled to into 0～5 DEG C, 2260 mL n-hexanes is added dropwise in grease under stirring, 0～5
Continue stirring 1.5 hours at DEG C.A large amount of White crystalline solids are separated out, suction filtration is washed with 0～5 DEG C of n-hexane of 100ml, 30 DEG C
It is dried to constant weight in vacuum drying chamber, obtains white crystalline green card color woods hydrochloride semi-hydrate crystal formation solid 109.2g, yield
93.0%, purity 99.4%.By differential scanning calorimetry（DSC）Sample crystal formation is characterized, in DSC curve, about 94 DEG C
With 202 DEG C at have endothermic peak at two respectively, wherein 94 DEG C for dehydration peak, 202 DEG C be sample melted peak.
Embodiment three
（a）The preparation of green card color woods hydrochloride
At 0～5 DEG C, to 100.0g（0.51mol）500mL absolute methanols are added in green card color woods free alkali（Moisture
0.1%）, stir to clarify after making to be completely dissolved, be slowly introducing in reactant liquor dry hydrogen chloride gas until saturation after, 30
Remove absolute methanol at DEG C under reduced pressure and obtain off-white powder shape green card color woods HCl, solid 116.3g, yield 98.0%.
（b）The preparation of green card color woods hydrochloride semi-hydrate crystal formation
（1）At 25～30 DEG C, to 116.3g（0.5mol）600mL absolute ethyl alcohols are added in green card color woods hydrochloride（Water
Divide 0.3%）, stir to clarify after making to be completely dissolved, add 5.0g（0.278mol）Distilled water, after stirring 1 hour, subtracts at 30 DEG C
Pressure distillation carries out concentration and removes solvent, obtains sticky grease.
（2）Sticky grease is cooled to into 0～5 DEG C, 1163mL acetone is added dropwise in grease under stirring, at 0～5 DEG C
Continue stirring 1 hour.A large amount of White crystalline solids are separated out, suction filtration is washed with 0～5 DEG C of acetone of 100ml, 30 DEG C of vacuum drying
It is dried to constant weight in case, obtains white crystalline green card color woods hydrochloride semi-hydrate crystal formation solid 117.2g, yield 97.0% is pure
Degree 99.4%.Product Jing DSC are characterized and are confirmed as green card color woods hydrochloride semi-hydrate crystal formation.
Example IV
（a）The preparation of green card color woods hydrochloride
At 0～5 DEG C, to 100.0g（0.51mol）2000mL absolute ethyl alcohols are added in green card color woods free alkali（Moisture
0.3%）, stir to clarify after making to be completely dissolved, be slowly introducing in reactant liquor dry hydrogen chloride gas until saturation after, 30
Remove absolute ethyl alcohol at DEG C under reduced pressure and obtain off-white powder shape green card color woods HCl, solid 116.3g, yield 98.0%.
（b）The preparation of green card color woods hydrochloride semi-hydrate crystal formation
（1）At 25～30 DEG C, to 116.3g（0.5mol）2326mL absolute ethyl alcohols are added in green card color woods hydrochloride（Water
Divide 0.3%）, stir to clarify after making to be completely dissolved, add 5.0g（0.278mol）Distilled water, after stirring 3 hours, subtracts at 30 DEG C
Pressure distillation carries out concentration and removes solvent, obtains sticky grease.
（2）Sticky grease is cooled to into 0～5 DEG C, stirring is lower to instill 3489mL petroleum ethers, continues stirring at 0～5 DEG C
3 hours.A large amount of White crystalline solids are separated out, suction filtration, with 0～5 DEG C of petroleum ether of 100ml, is done in 30 DEG C of vacuum drying chambers
It is dry to constant weight, obtain white crystalline green card color woods hydrochloride semi-hydrate crystal formation solid 117.2g, yield 97.0%, purity
99.4%.Product Jing DSC are characterized and are confirmed as green card color woods hydrochloride semi-hydrate crystal formation.
Claims (12)
1. a kind of preparation method of green card color woods hydrochloride semi-hydrate crystal formation, it is characterised in that methods described includes following step
Suddenly：
(1), after be dissolved completely in green card color woods hydrochloride in the first organic solvent, water, stirring, concentration is added to remove solvent, obtain
To grease；
(2) the second organic solvent is added in the grease, stir, obtain green card color woods hydrochloride semi-hydrate crystal formation；
The one kind of first organic solvent in absolute methanol, absolute ethyl alcohol, isopropanol, dichloromethane；Described second has
The one kind of machine solvent in toluene, n-hexane, hexamethylene, petroleum ether, ethyl acetate, acetone；
Described green card color woods hydrochloride semi-hydrate crystal formation, in the X-ray powder diffraction collection represented with 2 θ angles, bag
Include 10.3,12.7,13.7,14.9,15.5,15.8,16.7,18.5,18.9,19.2,20.0,20.5,21.4,22.8,
23.2nd, 23.4,24.0,24.8,25.4,25.7,26.6,26.9,27.5,28.2,29.0 have main diffraction maximum, the 2 θ angles
Error range ± 0.2.
2. the preparation method of a kind of green card color woods hydrochloride semi-hydrate crystal formation according to claim 1, it is characterised in that：
The preparation method of the green card color woods hydrochloride is that green card color woods free alkali is dissolved completely in after the 3rd organic solvent, to reaction
Hydrogen chloride gas are passed through in liquid until after saturation, removing the 3rd organic solvent and obtaining green card color woods hydrochloride, the described 3rd is organic
The one kind of solvent in absolute methanol, absolute ethyl alcohol, isopropanol, dichloromethane, acetone, ether.
3. the preparation method of a kind of green card color woods hydrochloride semi-hydrate crystal formation according to claim 1, it is characterised in that：
First organic solvent is selected from dichloromethane；Second organic solvent is selected from ethyl acetate.
4. the preparation method of a kind of green card color woods hydrochloride semi-hydrate crystal formation according to claim 1, it is characterised in that：
Described green card color woods hydrochloride semi-hydrate crystal formation has X-ray powder diffraction collection substantially as shown in Figure 1.
5. the preparation method of a kind of green card color woods hydrochloride semi-hydrate crystal formation according to claim 1, it is characterised in that：
Described green card color woods hydrochloride semi-hydrate crystal formation has in Differential Scanning Calorimetry at about 94 DEG C and 202 DEG C respectively
Endothermic peak at two, wherein 94 DEG C are dehydration peak, 202 DEG C is sample melted peak.
6. the preparation method of a kind of green card color woods hydrochloride semi-hydrate crystal formation according to claim 1, it is characterised in that：
The weight of described green card color woods hydrochloride is 1 with the volume ratio of the first organic solvent:5～1:20, described green card color woods salt
The weight of hydrochlorate is 1 with the volume ratio of the second organic solvent:10～1:30, the unit of the quality for gram, the list of the volume
Position is milliliter, and described green card color woods hydrochloride and the mol ratio of water are 1:0.5～1:0.6.
7. the preparation method of a kind of green card color woods hydrochloride semi-hydrate crystal formation according to claim 2, it is characterised in that：
The quality of the green card color woods free alkali is 1 with the volume ratio of the 3rd organic solvent:5～1:20, the unit of the quality for gram,
The unit of the volume is milliliter；The aqueous weight content of the 3rd described organic solvent is less than 0.5%；It is described by green card color woods
After free alkali is dissolved completely in the 3rd organic solvent, hydrogen chloride gas are passed through in reactant liquor until the temperature of the process of saturation is
0～5 DEG C；3rd organic solvent is selected from dichloromethane.
8. the preparation method of a kind of green card color woods hydrochloride semi-hydrate crystal formation according to claim 1, it is characterised in that：
In step (1), the temperature being completely dissolved is 25～30 DEG C, and the time being stirred after adding water is 1-3 hours；It is described
The mode of concentration is vacuum distillation, and the temperature of the vacuum distillation is 25～30 DEG C；The aqueous weight of first organic solvent
Content is less than 0.5%.
9. the preparation method of a kind of green card color woods hydrochloride semi-hydrate crystal formation according to claim 1, it is characterised in that：
In step (2), the temperature of the grease is 0～5 DEG C, and the mode that the second organic solvent is added in the grease is drop
Plus, the temperature during stirring is 0～5 DEG C, and the time of the stirring is 1-3 hours, also includes filtering, washes after the stirring
Wash, be dried step, the washing adopt for the second organic solvent.
10. the preparation method of a kind of green card color woods hydrochloride semi-hydrate crystal formation according to claim 2, its feature exist
In：Described hydrogen chloride gas are dry hydrogen chloride gas, and the mode for being passed through hydrogen chloride gas is to be slowly introducing, described
The mode of the 3rd organic solvent is removed to remove under reduced pressure, the temperature for removing under reduced pressure is 25～30 DEG C.
A kind of 11. preparation methods of green card color woods hydrochloride semi-hydrate crystal formation according to claim 7, its feature exist
In：The aqueous weight content of the 3rd described organic solvent is less than 0.2%.
A kind of 12. preparation methods of green card color woods hydrochloride semi-hydrate crystal formation according to claim 8, its feature exist
In：The aqueous weight content of first organic solvent is less than 0.2%.
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