CN107963991A - A kind of production method of amorphous tolvaptan - Google Patents
A kind of production method of amorphous tolvaptan Download PDFInfo
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- CN107963991A CN107963991A CN201711474183.0A CN201711474183A CN107963991A CN 107963991 A CN107963991 A CN 107963991A CN 201711474183 A CN201711474183 A CN 201711474183A CN 107963991 A CN107963991 A CN 107963991A
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- GYHCTFXIZSNGJT-UHFFFAOYSA-N Cc1ccccc1C(Nc(cc1)cc(C)c1C(N(CCCC1O)c(cc2)c1cc2Cl)=O)=O Chemical compound Cc1ccccc1C(Nc(cc1)cc(C)c1C(N(CCCC1O)c(cc2)c1cc2Cl)=O)=O GYHCTFXIZSNGJT-UHFFFAOYSA-N 0.000 description 1
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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
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- Plural Heterocyclic Compounds (AREA)
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Abstract
The invention discloses a kind of production method of amorphous tolvaptan, comprise the following steps：A. it will be mixed with solvent I for the tolvaptan solution of solvent with solvent II, separate out solid content, wherein, solvent I is the good solvent of tolvaptan, and solvent II is the poor solvent of tolvaptan；B. the solid content of step of learning from else's experience a, is washed with solvent III, and suspended matter is made into solvent IV in redisperse, by freeze-drying, obtains amorphous tolvaptan；Solvent III, the poor solvent that IV is tolvaptan；The production method of the present invention make it that prepared amorphous tolvaptan product quality is more stable, while is also more suitable for amplification production, and the popularization to the medicine can play more positive effect.
Description
Technical field
The present invention relates to amorphous tolvaptan field, more particularly to a kind of production method of amorphous tolvaptan.
Background technology
Tolvaptan is a kind of oral non-peptides vasopressin V 2 Receptor Antagonists developed by Japanese great Zhong drugmakers,
Listed respectively in US and European within 2009, trade name：SAMSCA, is mainly used for treating heart failure, hepatic sclerosis and antidiuresis
The hyponatremia of hormone secretion deficiency syndrome patient.
Tolvaptan chemical name：N- [4- [chloro- 5- hydroxyls -2,3,4,5- tetrahydrochysenes -1H- benzos [b] azatropylidenes of (5RS) -7- -
1- formoxyls] -3- aminomethyl phenyls] -2- methyl benzamides, its structural formula is as follows：
Classified according to BCS, tolvaptan belongs to IV classes, i.e., low molten hypotonic medicine.The change is found during preparation research
The unbodied dissolution rate of compound is substantially better than crystal-form compound.The preparation method of existing tolvaptan crystal is general by the way that support is cut down
It is smooth to be dissolved in the mixed solvent spray drying of dichloromethane and lower alcohol with hydroxypropyl cellulose 1: 1 weight ratio and formed amorphous
Composition.Above-mentioned amorphous composite, due to containing specific auxiliary material, greatly limit the preparation research in later stage, being unfavorable for producing
The popularization of product.The preparation method of amorphous tolvaptan is referred in Chinese patent CN103880747, this method is without using extra auxiliary
Material, it is easier to operate.
The content of the invention
The preparation method that amorphous tolvaptan is referred in Chinese patent CN103880747 is repeated early period in inventor,
Under production scale disclosed in the patent, amorphous tolvaptan can actually be prepared, but it was unexpectedly observed that by its method
After amplification production, what is finally obtained is the mixture of the amorphous and crystal habit of tolvaptan (referring to reference example of the present invention
1、2)。
In order to overcome the shortcomings of it is above-mentioned have been surprisingly found that, inventor is finally obtained by substantial amounts of experiment screening and contrast
A kind of method for being more suitable for production amplification prepares amorphous tolvaptan, and this method can make the amorphous tolvaptan of preparation
Quality is more stable.
Specifically, the present invention provides a kind of production method of amorphous tolvaptan, comprise the following steps：
A. it will be mixed with solvent I for the tolvaptan solution of solvent with solvent II, separate out solid content, wherein, solvent I is support
General smooth good solvent is cut down, solvent II is the poor solvent of tolvaptan；
B. the solid content of step of learning from else's experience a, is washed with solvent III, and suspended matter is made into solvent IV in redisperse, by freezing
It is dry, obtain amorphous tolvaptan；Solvent III, the poor solvent that IV is tolvaptan.
In the present invention, the solvent III, IV are not only the poor solvent of tolvaptan, and are suitable for being freeze-dried.
" the tolvaptan solution with solvent I for solvent ", its source can be prepared by conventional soln manner of formulation,
Can be the solution containing high-purity tolvaptan of acquisition by the prior art during tolvaptan is prepared.
If prepared by conventional soln manner of formulation, need using solid tolvaptan as raw material, which can
To be the crystal-form compound or tolvaptan mixed crystal of tolvaptan, the mixed crystal includes the mixing of a variety of crystal forms, also wraps
Include amorphous and crystal form thing mixing.
Heretofore described high-purity, refers to meet the general level of color or pharmaceutical grade purity requirement.
In an embodiment of the invention, all steps before freeze-drying can use the prior art
Method, such as Chinese patent CN103880747.
The good solvent of tolvaptan just refers to the solvent good to tolvaptan dissolubility in the present invention, otherwise is cut down for support
General smooth poor solvent.
Wherein, the solvent I be selected from methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, ethyl acetate, acetonitrile,
One or more mixtures in n,N-Dimethylformamide, dimethyl sulfoxide.
Wherein, the solvent II is selected from water, n-hexane, normal heptane, hexamethylene, petroleum ether, tetrahydrofuran, ether, isopropyl
One or more mixtures in ether, methyl tertiary butyl ether(MTBE).
Certainly, more precipitation in order to enable target product is tried one's best, selects dissolving each other as far as possible between solvent I and solvent II,
Be conducive to the precipitation of solid content.
Wherein, the solvent III, IV are water.
Further, the solvent I is selected from acetone, methanol, ethanol, ethyl acetate, the one or more of dichloromethane and mixes
Compound, is further methanol or ethanol.
Further, the solvent II is selected from water, n-hexane, petroleum ether, is preferably water or n-hexane.
Further, in step a, tolvaptan solution is not cooled down or is added to after cooling down in solvent II, adition process or/
With adjoint stirring in solid content precipitation process.Mixing speed can routinely understanding carries out appropriate adjusting according to this area, can be with
It is to mix slowly or quickly stir.
In the present invention, tolvaptan solution can be added rapidly in solvent II.Above-mentioned " rapidly joining " refers to quickly
Dropwise addition or direct rapid dumps, fast drop time or dumping time are 0~10 minute (not including 0 minute).Wherein, it is described cold
Freeze drying condition as cooling 15~45 minutes to -35~-55 DEG C；When remaining -35~-55 DEG C 1~3 small；Maintain -35~-55 DEG C
Decompression vacuum pumping 10~30 minutes is to 10~25Pa；Heat up 50~70 minutes to -6~-16 DEG C under the conditions of 10~25Pa；Maintain -6
~-16 DEG C, 10~25Pa, 10~20 it is small when；50~70 minutes decompression vacuum pumpings are warming up to 30~50 DEG C to 3~7Pa；
Maintain 30~50 DEG C, 4~6Pa, 4~7 it is small when.
In an embodiment of the invention, freeze-drying condition is cooling 30 minutes to -45 DEG C；Maintain -45 DEG C 2 small
When；- 45 DEG C of decompression vacuum pumpings 20 minutes are maintained to 15~20Pa；Heat up 60 minutes to -10 DEG C under the conditions of 15~20Pa；Maintain-
10 DEG C, 15~20Pa, 15 it is small when；60 minutes decompression vacuum pumpings are warming up to 40 DEG C to 5Pa；Maintain 40 DEG C, 5Pa, 6 it is small when.
In an embodiment of the invention, freeze-drying condition is cooling 45 minutes to -55 DEG C；Maintain -55 DEG C 1 small
When；- 55 DEG C of decompression vacuum pumpings 10 minutes are maintained to 10~15Pa；Heat up 70 minutes to -16 DEG C under the conditions of 10~15Pa；Maintain-
16 DEG C, 10~15Pa, 10 it is small when；70 minutes decompression vacuum pumpings are warming up to 30~35 DEG C to 7Pa；30~35 DEG C are maintained,
4Pa, 7 it is small when.
In an embodiment of the invention, freeze-drying condition is cooling 15 minutes to -35 DEG C；Maintain -35 DEG C 3 small
When；- 35 DEG C of decompression vacuum pumpings 30 minutes are maintained to 20~25Pa；Heat up 50 minutes to -6 DEG C under the conditions of 20~25Pa；Maintain -6
DEG C, 20~25Pa, 20 it is small when；50 minutes decompression vacuum pumpings are warming up to 45~50 DEG C to 3Pa；45~50 DEG C, 6Pa are maintained,
4 it is small when.
After step a separates out solid content, solid content can be separated with solvent using conventional means, conventional method is included but not
It is limited to filter or centrifuges.
Wherein, the ratio of the tolvaptan crystal-form compound and solvent I is 1g:5~50mL, one specific implementation of the present invention
In mode, which can be selected from 1g:10~16mL, such as 1g:10mL、1g:11mL、1g:12mL、1g:13mL、1g:14mL、
1g:15mL、1g:16mL。
Wherein, II volume of solvent is 0.5~15 times of I volume of solvent, is further selected from 0.5-5 times.The present invention one
In a embodiment, which can be selected from 2~3 times.
Wherein, the temperature of the solvent II is 0~10 DEG C, and in an embodiment of the invention, which can select
From from 0~6 DEG C, such as 0 DEG C, 1 DEG C, 2 DEG C, 3 DEG C, 4 DEG C, 5 DEG C, 6 DEG C.
Wherein, it is described mixed with solvent II after continue stirring time be 0~15 minute.
The reasonable error scope of above-mentioned numerical value, it should also be included within protection scope of the present invention.
Confirmed in present invention research, nothing can be prepared after amplification produces according to the method for Chinese patent CN103880747
Shape tolvaptan, but can be seen that different conditions from each embodiment and reference example, the generation to amorphous tolvaptan
Have a certain impact.
Compared with prior art, under conditions of with good yield, the present invention is passing through dissolution phase and precipitation phase
Afterwards, using freeze-drying so that prepared amorphous tolvaptan quality is more stable, it is suppressed that crystal phenomenon occurs, explanation
The method of the present invention is more suitable for amplification production, and the popularization to the medicine can play more positive effect.
Brief description of the drawings
Fig. 1 is the XRD diagram of tolvaptan obtained by reference example 1 of the present invention；
Fig. 2 is the DSC figures of tolvaptan obtained by reference example 1 of the present invention, TGA figures；
Fig. 3 is the XRD diagram of tolvaptan obtained by reference example 2 of the present invention；
Fig. 4 is the DSC figures of tolvaptan obtained by reference example 2 of the present invention, TGA figures；
Fig. 5 is the XRD diagram of the amorphous tolvaptan of the present invention；
Fig. 6 is the DSC figures of the amorphous tolvaptan of the present invention, TGA figures.
Embodiment
In order to make the purpose , technical scheme and advantage of the present invention be clearer, below in conjunction with attached drawing and reference example, reality
Example is applied, the present invention will be described in further detail.It should be appreciated that specific embodiment described herein is only explaining this hair
It is bright, it is not intended to limit the present invention.
After using tolvaptan to prepare tolvaptan solution for raw material in the specific embodiment of the invention, then prepare without fixed
Shape tolvaptan.
Tolvaptan raw material can be obtained by buying commercially available production piece, can also be prepared with reference to the prior art, such as such as
Lower technique：
4.48L dichloromethane and 18.24L ethanol are added into 50L double-layer glass reaction kettles, stirs lower addition 3.2kg7-
Chloro- 1- [2- methyl -4- (2- methylbenzoylamin. os) benzoyl] -2,3,4,5- tetrahydro-1 H-1-benzazepino-5-ketones, instead
Thing is answered to suspend stirring, it is point multiple batches of to be slowly added to 230.4g potassium borohydrides controlled at 15~25 DEG C, controlled at 20~
When 25 DEG C of stirrings 5 are small, the aqueous hydrochloric acid solution 10L for being added dropwise 0.5% terminates reaction, allows mixture when 20~25 DEG C of stirrings 1 are small, with
When postcooling keeps 0~5 DEG C of stirring 4 small, filter solid is crossed, 50~60 DEG C are dried under reduced pressure to constant weight, obtain tolvaptan 2944g,
Its fusing point is 223~225 DEG C.
400-MHz 1H NMR(DMSO-d6)：δ=1.48 (m, 1H), 1.77 (d, 1H), 1.96 (m, 1H), 2.10 (d,
1H), 2.37 (s, 6H), 2.68 (t, 1H), 4.64 (d, 1H), 4.91 (d, 1H), 5.72 (m, 1H), 6.75 (d, 1H), 6.77 (t,
1H), 7.04 (d, 1H), 7.28 (m, 3H), 7.36 (m, 1H), 7.41 (d, 1H), 7.53 (d, 1H), 7.59 (s, 1H), 10.27
(s, 1H).
Reference example 1
500mL methanol, 50g tolvaptan crystal-form compounds are added into 1L reaction bulbs, heating stirring is obtained to being completely dissolved
Methanol-tolvaptan solution, naturally cooled under stirring 35 DEG C it is spare.
The water (temperature is 5 DEG C) that 1.5L has been pre-cooled is added into 5L reaction bulbs, under quick stirring, pours into above-mentioned support
General smooth solution to be cut down, separates out a large amount of solids at once, after toppling over, continues stirring 5 minutes, filtering, 50 DEG C are dried under reduced pressure to constant weight,
Obtain 45.7g tolvaptans.
Reference example 2
5L methanol, 500g tolvaptan crystal-form compounds are added into 10L reaction bulbs, heating stirring is obtained to being completely dissolved
Methanol-tolvaptan solution, naturally cooled under stirring 35 DEG C it is spare.
The water (temperature is 5 DEG C) that 15L has been pre-cooled is added into 50L double-layer glass reaction kettles, under quick stirring, is toppled over
Enter above-mentioned tolvaptan solution, separate out a large amount of solids at once, after toppling over, continue stirring 5 minutes, filtering, 50 DEG C of decompressions are done
It is dry to constant weight, obtain 460g tolvaptans.
Crystal form detection is carried out to tolvaptan obtained by above-mentioned reference example, XRD detects two equal nothings of embodiment products obtained therefrom
Obvious characteristic peak；Heat analysis detection is further carried out, sample obtained by reference example 1 (Chinese patent CN103880747 lab scales) is only
There is obvious endothermic peak in decomposition temperature, show the sample to be pure amorphous, and reference example 2 (amplification production) gained sample
There are two obvious endothermic peaks before decomposition temperature, show to contain crystal tolvaptan in the sample, simply its amount is smaller, so
Without obvious characteristic peak in XRD detections.Research shows, using dissolving, the technique for separating out, being commonly dried under reduced pressure when measuring less
Wait, pure amorphous tolvaptan can be made, but after inventory is amplified, will be mixed with crystal tolvaptan in products obtained therefrom, say
There is some processes condition to be not suitable for amplification production in the technique of bright Chinese patent CN103880747.
Embodiment 1
9L acetone, 300g tolvaptan crystal-form compounds are added into 10L reaction bulbs, heating stirring is obtained to being completely dissolved
Acetone-tolvaptan solution, naturally cooled under stirring 25 DEG C it is spare.
The n-hexane (temperature is 4 DEG C) that 36L has been pre-cooled is added into 50L double-layer glass reaction kettles, under quick stirring,
In 5 minutes, to the above-mentioned acetone of n-hexane fast drop-tolvaptan solution, a large amount of solids are separated out at once, after being added dropwise, after
Continuous stirring 15 minutes, filtering, and 600ml water washing filter cakes are used, again after filtering, gained filter cake is transferred to equipped with 4.5L water
In reaction bulb, after stirring becomes uniform suspension in 5 minutes, gained suspension is transferred to lyophilized plate freeze-drying, is obtained
The amorphous tolvaptans of 252g.
Embodiment 2
10L methanol, 1kg tolvaptan crystal-form compounds are added into 20L reaction bulbs, heating stirring is obtained to being completely dissolved
Obtain methanol-tolvaptan solution for standby.
The water (temperature is 5 DEG C) that 30L has been pre-cooled is added into 50L double-layer glass reaction kettles, under quick stirring, is toppled over
Enter above-mentioned tolvaptan solution, separate out a large amount of solids at once, after toppling over, continue stirring 10 minutes, centrifugation, and washed with 2L
Filter cake is washed, after centrifuging again, gained filter cake is transferred in the reaction bulb equipped with 5L water, stirring becomes uniform for 5 minutes
After suspension, gained suspension is transferred to lyophilized plate freeze-drying, obtains the amorphous tolvaptans of 924g.
Embodiment 3
8L ethanol, 500g tolvaptan crystal-form compounds are added into 10L reaction bulbs, heating stirring is obtained to being completely dissolved
Ethanol-tolvaptan solution, naturally cooled under stirring 40 DEG C it is spare.
The water (temperature is 6 DEG C) that 20L has been pre-cooled is added into 50L double-layer glass reaction kettles, under quick stirring, 10 points
In clock, fast drop enters above-mentioned ethanol-tolvaptan solution, separates out a large amount of solids at once, after being added dropwise, continues 15 points of stirring
Clock, centrifugation, and use 1L water washing filter cakes, again centrifuge after, gained filter cake is transferred in the reaction bulb equipped with 2.5L water, stirring
After 5 minutes become uniform suspension, gained suspension is transferred to lyophilized plate freeze-drying, the amorphous supports of 468g is obtained and cuts down
Pu Tan.
Embodiment 4
15L ethyl acetate, 3L dichloromethane, 500g tolvaptan crystal-form compounds are added into 20L reaction bulbs, heating is stirred
Mix to being completely dissolved, obtain mixed solution, naturally cooled under stirring 35 DEG C it is spare.
The petroleum ether (temperature is 0 DEG C) that 54L has been pre-cooled, quick stirring are added into 100L double-layer glass reaction kettles
Under, above-mentioned mixed solution is poured into, separates out a large amount of solids at once, continues stirring 5 minutes, filtering, and with 1L water washing filter cakes, then
After secondary filtering, gained filter cake is transferred in the reaction bulb equipped with 8L water, after stirring becomes uniform suspension in 5 minutes,
Gained suspension is transferred to lyophilized plate freeze-drying, obtains the amorphous tolvaptans of 434g.
It is initial cooling 30 minutes to -45 DEG C that condition is freeze-dried in above-described embodiment；And when remaining -45 DEG C 2 small；So
- 45 DEG C of decompression vacuum pumpings 20 minutes are maintained afterwards to 15~20Pa；Heat up 60 minutes to -10 DEG C under the conditions of 15~20Pa；Maintain -10
DEG C, 15~20Pa 15 it is small when；60 minutes decompression vacuum pumpings are warming up to 40 DEG C to 5Pa；When 40 DEG C of maintenance, 5Pa 6 are small.
The present invention can also with the mixture of dimethyl sulfoxide or dimethyl sulfoxide and the solvent I used in embodiment 1~4 come
Tolvaptan crystal-form compound is dissolved, can also be replaced using in embodiment 1~4 with normal heptane, hexamethylene, ether, isopropyl ether
Solvent II separate out the solid in solution.
Fig. 1~4 are tolvaptan XRD, DSC, TGA collection of illustrative plates prepared by reference example of the present invention；Fig. 5~6 are systems of the present invention
XRD, DSC, TGA collection of illustrative plates of standby unformed tolvaptan.It can be seen that with reference to XRD and heat analysis trace analysis using existing
After method in technology is amplified production, its product is the amorphous and mixture of crystal form, illustrates there is crystal phenomenon；And
The method of the present invention is produced greatly, and the stability of amorphous products is preferable, effectively inhibits the crystal phenomenon of original technique.
In addition, it is higher to can be seen that the yield after the method for the present invention amplification production from above-described embodiment.
Although reference be made herein to invention has been described for multiple explanatory embodiments of the invention, however, it is to be understood that
Those skilled in the art can be designed that a lot of other modifications and embodiment, these modifications and embodiment will fall in this Shen
Please be within disclosed spirit and spirit.More specifically, can in the range of disclosure, drawings and claims
A variety of variations and modifications are carried out with the building block to theme combination layout and/or layout.Except to building block and/or layout
Outside the variations and modifications of progress, to those skilled in the art, other purposes also will be apparent.
The foregoing is merely the embodiment of the present invention, is not intended to limit the scope of the invention, every to utilize this hair
The equivalent structure or equivalent flow shift that bright description is made, is directly or indirectly used in other relevant technology necks
Domain, is included within the scope of the present invention.
Claims (10)
1. a kind of production method of amorphous tolvaptan, it is characterised in that comprise the following steps：
A. it will be mixed with solvent I for the tolvaptan solution of solvent with solvent II, separate out solid content, wherein, solvent I cuts down general for support
Smooth good solvent, solvent II are the poor solvent of tolvaptan；
B. the solid content of step of learning from else's experience a, is washed with solvent III, and suspended matter is made into solvent IV in redisperse, by freeze-drying,
Obtain amorphous tolvaptan；Solvent III, the poor solvent that IV is tolvaptan.
2. the production method of a kind of amorphous tolvaptan according to claim 1, it is characterised in that the solvent I selects
From methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, ethyl acetate, acetonitrile, n,N-Dimethylformamide, dimethyl sulfoxide
In one or more mixtures；The solvent II be selected from water, n-hexane, normal heptane, hexamethylene, petroleum ether, tetrahydrofuran,
One or more mixtures in ether, isopropyl ether, methyl tertiary butyl ether(MTBE)；The solvent III, IV are water.
3. the production method of a kind of amorphous tolvaptan according to claim 2, it is characterised in that the solvent I selects
From acetone, methanol, ethanol, ethyl acetate, dichloromethane one or more mixtures, be further methanol or ethanol.
4. the production method of a kind of amorphous tolvaptan according to claim 1, it is characterised in that the solvent II selects
It is further water or n-hexane from water, n-hexane, petroleum ether.
5. the production method of a kind of amorphous tolvaptan according to claim 1, it is characterised in that in step a, support is cut down
General smooth solution is not cooled down or is added to after cooling down in solvent II, with stirring in adition process or/and solid content precipitation process；Into
One step, tolvaptan solution is added rapidly in solvent II.
A kind of 6. production method of amorphous tolvaptan according to claim 5, it is characterised in that the cooling butt
The temperature for cutting down general smooth solution is 25~40 DEG C.
A kind of 7. production method of amorphous tolvaptan according to claim 1, it is characterised in that the freeze-drying
Condition is cooling 15 ~ 45 minutes to -35 ~ -55 DEG C；When remaining -35 ~ -55 DEG C 1 ~ 3 small；Maintain -35 ~ -55 DEG C of decompression vacuum pumpings 10
~ 30 minutes to 10 ~ 25Pa；Heat up 50 ~ 70 minutes to -6 ~ -16 DEG C under the conditions of 10 ~ 25Pa；- 6 ~ -16 DEG C, 10 ~ 25Pa are maintained,
10 ~ 20 it is small when；50 ~ 70 minutes decompression vacuum pumpings are warming up to 30 ~ 50 DEG C to 3 ~ 7Pa；30 ~ 50 DEG C, 4 ~ 6Pa of maintenance, 4 ~ 7
Hour.
A kind of 8. production method of amorphous tolvaptan according to claim 1, it is characterised in that the tolvaptan
The ratio of crystal-form compound and solvent I is 1g:5~50mL, is further 1g:10~16 mL.
A kind of 9. production method of amorphous tolvaptan according to claim 1, it is characterised in that II body of solvent
Product is 0.5~15 times of I volume of solvent, is further 2 ~ 3 times.
A kind of 10. production method of amorphous tolvaptan according to claim 1, it is characterised in that the solvent II
Temperature be 0~10 DEG C, be further 0 ~ 6 DEG C.
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Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1625394A (en) * | 2001-12-28 | 2005-06-08 | 拜奥盖尔药厂有限公司 | Processes for preparing crystalline and amorphous mupirocin calcium |
| CN101103024A (en) * | 2005-03-21 | 2008-01-09 | 卫材R&D管理有限公司 | Pyrimidine compound crystal or amorphous form and process for producing the same |
| CN101330905A (en) * | 2005-11-18 | 2008-12-24 | 赛多斯有限责任公司 | Lyophilization process and products obtained thereby |
| CN101573351A (en) * | 2006-11-29 | 2009-11-04 | 武田药品工业株式会社 | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| CN103880747A (en) * | 2014-03-20 | 2014-06-25 | 成都百裕科技制药有限公司 | Method for preparing amorphous tolvaptan |
| CN104230808A (en) * | 2014-08-22 | 2014-12-24 | 苏州亚宝药物研发有限公司 | Amorphous ivabradine hydrochloride, and preparation method and application thereof |
| IN2013MU02093A (en) * | 2013-06-20 | 2015-06-05 | Enaltec Labs Private Ltd | |
| CN104829530A (en) * | 2015-04-23 | 2015-08-12 | 扬子江药业集团北京海燕药业有限公司 | Amorphous ivabradine hydrochloride and preparation method thereof |
| CN106518709A (en) * | 2016-11-07 | 2017-03-22 | 济南益新医药技术有限公司 | Preparation method of amorphous sacubitri valsartan sodium salt composite |
-
2017
- 2017-12-29 CN CN201711474183.0A patent/CN107963991A/en active Pending
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1625394A (en) * | 2001-12-28 | 2005-06-08 | 拜奥盖尔药厂有限公司 | Processes for preparing crystalline and amorphous mupirocin calcium |
| CN101103024A (en) * | 2005-03-21 | 2008-01-09 | 卫材R&D管理有限公司 | Pyrimidine compound crystal or amorphous form and process for producing the same |
| CN101330905A (en) * | 2005-11-18 | 2008-12-24 | 赛多斯有限责任公司 | Lyophilization process and products obtained thereby |
| CN101573351A (en) * | 2006-11-29 | 2009-11-04 | 武田药品工业株式会社 | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| IN2013MU02093A (en) * | 2013-06-20 | 2015-06-05 | Enaltec Labs Private Ltd | |
| CN103880747A (en) * | 2014-03-20 | 2014-06-25 | 成都百裕科技制药有限公司 | Method for preparing amorphous tolvaptan |
| CN104230808A (en) * | 2014-08-22 | 2014-12-24 | 苏州亚宝药物研发有限公司 | Amorphous ivabradine hydrochloride, and preparation method and application thereof |
| CN104829530A (en) * | 2015-04-23 | 2015-08-12 | 扬子江药业集团北京海燕药业有限公司 | Amorphous ivabradine hydrochloride and preparation method thereof |
| CN106518709A (en) * | 2016-11-07 | 2017-03-22 | 济南益新医药技术有限公司 | Preparation method of amorphous sacubitri valsartan sodium salt composite |
Non-Patent Citations (1)
| Title |
|---|
| 蔡津生，卢国宝: "《中国食药用菌工程学》", 31 January 2015, 上海科学技术文献出版社 * |
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