CN103880747A - Method for preparing amorphous tolvaptan - Google Patents
Method for preparing amorphous tolvaptan Download PDFInfo
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- CN103880747A CN103880747A CN201410106784.6A CN201410106784A CN103880747A CN 103880747 A CN103880747 A CN 103880747A CN 201410106784 A CN201410106784 A CN 201410106784A CN 103880747 A CN103880747 A CN 103880747A
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- 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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Abstract
The invention discloses a method for preparing amorphous tolvaptan. The method comprises the steps of dissolving a tolvaptan crystalline compound into a solvent I, cooling to the temperature of 25-40 DEG C, so as to obtain a tolvaptan solution, then, adding the obtained tolvaptan solution into a rapidly-stirred solvent II, continuing to stir for 5-15 minutes after the adding is completed, then, filtering and drying, thereby obtaining amorphous tolvaptan, wherein the weight/volume ratio of the tolvaptan crystalline compound to the solvent I is 1g: (5-50)mL, solid precipitation exists during adding, the dosage of the solvent II is 0.5-5 times that of the solvent I, and the temperature of the rapidly-stirred solvent II is kept at 0-5 DEG C. According to the method, through using different solvents respectively at a dissolution stage and a precipitation stage and controlling the temperature change and dosage of the solvents, the yield of amorphous tolvaptan can be higher; moreover, the method disclosed by the invention is simple, is easy in operation and has no need of using large-sized equipment, such as a fluidized bed and the like, thereby being capable of playing a more active role in popularizing the drug.
Description
Technical field
Embodiments of the present invention relate to organic technical field of medicine synthesis, and more specifically, embodiments of the present invention relate to a kind of preparation method of amorphous tolvaptan.
Background technology
Tolvaptan is a kind of oral non-peptide class vasopressin V 2 Receptor Antagonists by the exploitation of Japanese great Zhong drugmaker, within 2009, go on the market at US and European respectively, trade(brand)name: SAMSCA, the hyponatremia that is mainly used in treating the not enough syndrome patient of heart failure, liver cirrhosis and antidiuretic hormone secretion.
Tolvaptan chemical name: N-[4-[(5RS) the chloro-5-of-7-hydroxyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] azatropylidene-1-formyl radical]-3-aminomethyl phenyl]-2-methyl benzamide, its structural formula is as follows:
According to BCS classification, tolvaptan belongs to IV class, i.e. low molten hypotonic medicine.In preparation research process, find that the unbodied dissolution rate of this compound is obviously better than crystal formation compound, can improve significantly drug quality and clinical efficacy, have great importance therefore study its amorphous products.The Chinese patent CN101273017 that is reported in of relevant tolvaptan crystal once had description, and fusing point is the anhydrous crystal thing of 226～227.5 DEG C.Relevant unbodied being described in world patent WO2009051022 mentioned its preparation method, by tolvaptan and the hydroxypropylcellulose weight ratio of 1: 1 being dissolved in to the dry amorphous composition that forms of mixed solvent spraying of methylene dichloride and lower alcohol, but in this preparation process, need to use the main equipments such as fluidized-bed, be unfavorable for preparation and the popularization of product; And the method for making of unformed tolvaptan is also described in Chinese patent application CN102020609, tolvaptan is added in anhydrous methanol, ethanol, acetone, dimethyl sulfoxide (DMSO) equal solvent, be heated to dissolve, filter, dry, obtain solid, i.e. amorphous tolvaptan, but use the shortcomings such as the method has length consuming time and yield is not high.
Summary of the invention
The present invention has overcome the deficiencies in the prior art, and a kind of preparation method's of amorphous tolvaptan embodiment is provided, and prepares amorphous tolvaptan with more economical more succinct method, makes the output of amorphous tolvaptan higher simultaneously.
For solving above-mentioned technical problem, one embodiment of the present invention by the following technical solutions:
A kind of preparation method of amorphous tolvaptan, comprise the steps: tolvaptan crystal formation compound dissolution in solvent I, to obtain tolvaptan solution, after cooling, described tolvaptan solution is added in the solvent II of rapid stirring, in adding procedure, there is solid to separate out, after having added, continue to be stirred to and separate out solid and no longer increase, then filter, dryly obtain amorphous tolvaptan.
Solvent I can effectively be dissolved tolvaptan crystal formation compound, and solvent II can allow the tolvaptan being dissolved in solvent I separate out fast, thereby reaches the object of the amorphous tolvaptan of quick preparation.
Further technical scheme is: described solvent I is the mixing solutions of a kind of in methyl alcohol, ethanol, Virahol, acetone, methylene dichloride, chloroform, ethyl acetate, acetonitrile, DMF, methyl-sulphoxide or two kinds.
Further technical scheme is: described solvent II is the one in water, normal hexane, normal heptane, hexanaphthene, sherwood oil, tetrahydrofuran (THF), ether, isopropyl ether, methyl tertiary butyl ether.
Further technical scheme is: the weight/volume of described tolvaptan crystal formation compound and solvent I is 1g:5～50mL.
Further technical scheme is: the volume of described solvent II is 0.5～5 times of volume of solvent I.
Further technical scheme is: the temperature of described cooling rear tolvaptan solution is 25～40 DEG C.
Further technical scheme is: the temperature of the solvent II of described rapid stirring is 0～5 DEG C.
Further technical scheme is: the time that after described interpolation completes, continuation is stirred is 5～15 minutes.
Further technical scheme is: the addition manner in described solvent II of gained tolvaptan solution being added to rapid stirring is for dripping fast or directly toppling over fast, and described time for adding or dumping time are no more than 5 minutes.
Compared with prior art, one of beneficial effect of the present invention is: the present invention is by using respectively different solvents in dissolution phase and precipitation phase, controlling solvent temperature changes and consumption, when making amorphous tolvaptan output reach 85～95%, its preparation method is simpler, and easy handling need not use the main equipments such as fluidized-bed, and can prepare fast the unformed tolvaptan with high clinical value, can play more positive effect to the popularization of this medicine.
Brief description of the drawings
Fig. 1 is the XRD figure of tolvaptan crystal formation compound of the present invention.
Fig. 2 is the XRD data sheet of Fig. 1.
Fig. 3 is the DSC figure of tolvaptan crystal formation compound of the present invention.
Fig. 4 is the TGA figure of tolvaptan crystal formation compound of the present invention.
Fig. 5 is the XRD figure of the amorphous tolvaptan of the present invention.
Fig. 6 is the DSC figure of the amorphous tolvaptan of the present invention.
Fig. 7 is and invents the TGA figure of amorphous tolvaptan.
Embodiment
In order to make object of the present invention, technical scheme and advantage clearer, below in conjunction with drawings and Examples, the present invention is further elaborated.Should be appreciated that specific embodiment described herein, only in order to explain the present invention, is not intended to limit the present invention.
The present invention prepares amorphous tolvaptan taking tolvaptan crystal formation compound as starting material, and tolvaptan crystal formation compound can be prepared by following method:
In 10L reaction flask, add 1120mL methylene dichloride and 4560mL ethanol, under stirring, add the chloro-1-[2-methyl-4-of 800g7-(2-toluyl amino) benzoyl]-2, 3, 4, 5-tetrahydro-1 H-1-benzazepino-5-ketone, reactant suspends and stirs, controlling temperature is 15～25 DEG C, divide the multiple batches of 57.6g POTASSIUM BOROHYDRIDE that slowly adds, controlling temperature is 20～25 DEG C of stirrings 5 hours, drip 0.5% aqueous hydrochloric acid 2500mL termination reaction, allow mixture stir 1 hour at 20～25 DEG C, 0～5 DEG C of stirring of cooling maintenance subsequently 4 hours, cross filter solid, 50～60 DEG C of drying under reduced pressure are to constant weight, obtain tolvaptan crystal formation compound 717g, as the tolvaptan crystal formation raw materials of compound in the following example 1-8, its fusing point is 223～225 DEG C.
400-MHz1H?NMR(DMSO-d6)：δ＝1.48(m，1H)，1.76(d，1H)，1.94(m，1H)，2.11(d，1H)，2.38(s，6H)，2.68(t，1H)，4.64(d，1H)，4.91(d，1H)，5.72(m，1H)，6.75(d，1H)，6.76(t，1H)，7.04(d，1H)，7.28(m，3H)，7.37(m，1H)，7.41(d，1H)，7.52(d，1H)，7.59(s，1H)，10.25(s，1H)。
In 2L reaction flask, add 1500mL acetone, 50g tolvaptan crystal formation compound, heated and stirred, to dissolving completely, obtains acetone-tolvaptan solution, under stirring, naturally cool to 25 DEG C for subsequent use.
In 10L reaction flask, add 6000mL cooling good normal hexane (temperature is 2 DEG C) in advance, under rapid stirring, in 5 minutes, drip fast above-mentioned acetone-tolvaptan solution to normal hexane, separate out at once a large amount of solids, after dropwising, continue to stir 15 minutes, filter, 60 DEG C of drying under reduced pressure are to constant weight, obtain the amorphous tolvaptan of 47.5g, productive rate reaches 95%.
In 1L reaction flask, add 500mL methyl alcohol, 50g tolvaptan crystal formation compound, heated and stirred, to dissolving completely, obtains methyl alcohol-tolvaptan solution, under stirring, naturally cool to 35 DEG C for subsequent use.
In 3L reaction flask, add 1500mL cooling good water (temperature is 5 DEG C) in advance, under rapid stirring, pour into above-mentioned tolvaptan solution, separate out at once a large amount of solids, after toppling over, continue to stir 5 minutes, filter, 50 DEG C of drying under reduced pressure, to constant weight, obtain the amorphous tolvaptan of 45.8g, and productive rate reaches 91.6%.
In 2L reaction flask, add 800mL ethanol, 50g tolvaptan crystal formation compound, heated and stirred, to dissolving completely, obtains ethanol-tolvaptan solution, under stirring, naturally cool to 40 DEG C for subsequent use.
In 5L reaction flask, add 2000mL cooling good water (temperature is 4 DEG C) in advance, under rapid stirring, in 5 minutes, be added dropwise to fast above-mentioned ethanol-tolvaptan solution, separate out at once a large amount of solids, after dropwising, continue to stir 15 minutes, filter, 60 DEG C of drying under reduced pressure are to constant weight, obtain the amorphous tolvaptan of 47g, productive rate reaches 94%.
In 3L reaction flask, add 1500mL ethyl acetate, 300mL methylene dichloride, 50g tolvaptan crystal formation compound, heated and stirred to completely dissolve, obtain mixing solutions, under stirring, naturally cool to 30 DEG C for subsequent use.
In 10L reaction flask, add 5400mL cooling good sherwood oil (temperature is 0 DEG C) in advance, under rapid stirring, pour into above-mentioned mixing solutions, separate out at once a large amount of solids, continue to stir 10 minutes, filter, 50 DEG C of drying under reduced pressure, to constant weight, obtain the amorphous tolvaptan of 48.6g, and productive rate reaches 97.2%.
Embodiment 5
In 2L reaction flask, add 750mL ethyl acetate, 250mL DMF, 50g tolvaptan crystal formation compound, heated and stirred to completely dissolve, obtain mixing solutions, under stirring, naturally cool to 25 DEG C for subsequent use.
In 10L reaction flask, add 5000mL cooling good sherwood oil (temperature is 5 DEG C) in advance, under rapid stirring, pour into above-mentioned tolvaptan solution, separate out at once a large amount of solids, continue to stir 5 minutes, filter, 55 DEG C of drying under reduced pressure are to constant weight, obtain the amorphous tolvaptan of 46.2g, productive rate reaches 92.4%.
Embodiment 6
In 1L reaction flask, add 200mL acetonitrile, 50mL methyl-sulphoxide, 50g tolvaptan crystal formation compound, heated and stirred to completely dissolve, under stirring, naturally cool to 30 DEG C for subsequent use.
In 3L reaction flask, add 125mL cooling good water (temperature is 1 DEG C) in advance, under rapid stirring, pour into above-mentioned tolvaptan solution, separate out at once a large amount of solids, continue to stir 5 minutes, filter, 60 DEG C of drying under reduced pressure, to constant weight, obtain the amorphous tolvaptan of 45.6g, and productive rate reaches 91.2%.
Embodiment 7
In 3L reaction flask, add 2500mL Virahol, 50g tolvaptan crystal formation compound, heated and stirred to completely dissolve, obtain Virahol-tolvaptan solution, under stirring, naturally cool to 40 DEG C for subsequent use.
In 5L reaction flask, add 1250mL cooling good tetrahydrofuran (THF) (temperature is 3 DEG C) in advance, under rapid stirring, pour into above-mentioned Virahol-tolvaptan solution, separate out at once a large amount of solids, continue to stir 5 minutes, filter, 50 DEG C of drying under reduced pressure are to constant weight, obtain the amorphous tolvaptan of 42.8g, productive rate reaches 85.6%.
In 2L reaction flask, add 1000mL chloroform, 250mL methyl alcohol, 50g tolvaptan crystal formation compound, heated and stirred to completely dissolve, obtain mixing solutions, under stirring, naturally cool to 35 DEG C for subsequent use.
In 5L reaction flask, add 1250mL cooling good methyl tertiary butyl ether (temperature is 5 DEG C) in advance, under rapid stirring, pour into above-mentioned tolvaptan solution, separate out at once a large amount of solids, continue to stir 5 minutes, filter, 55 DEG C of drying under reduced pressure are to constant weight, obtain the amorphous tolvaptan of 43.5g, productive rate reaches 87.0%.
The present invention can also be dissolved tolvaptan crystal formation compound with the mixture of the solvent I of using in ethanol or ethanol and embodiment 1～8, can also replace the solvent II of using in embodiment 1～8 that the solid in solution is separated out with normal heptane, hexanaphthene, ether, isopropyl ether.
The present invention prepares unformed tolvaptan with crystal formation tolvaptan, and Fig. 1～4th, crystal formation tolvaptan XRD used in the present invention, DSC, TGA collection of illustrative plates, wherein Fig. 2 is the data list of Fig. 1; Fig. 5～7th, XRD, the DSC of unformed tolvaptan prepared by the present invention, TGA collection of illustrative plates.
Although with reference to multiple explanatory embodiment of the present invention, invention has been described here, but, should be appreciated that, those skilled in the art can design a lot of other amendment and embodiments, within these amendments and embodiment will drop on the disclosed principle scope and spirit of the application.More particularly, in the scope of, accompanying drawing open in the application and claim, can carry out multiple modification and improvement to the building block of subject combination layout and/or layout.Except modification that building block and/or layout are carried out with improving, to those skilled in the art, other purposes will be also obvious.
Claims (9)
1. the preparation method of an amorphous tolvaptan, it is characterized in that: comprise the steps: tolvaptan crystal formation compound dissolution in solvent I, to obtain tolvaptan solution, after cooling, described tolvaptan solution is added in the solvent II of rapid stirring, in adding procedure, there is solid to separate out, after having added, continue to be stirred to and separate out solid and no longer increase, then filter, dryly obtain amorphous tolvaptan.
2. the preparation method of amorphous tolvaptan according to claim 1, it is characterized in that: described solvent I is the mixing solutions of a kind of in methyl alcohol, ethanol, Virahol, acetone, methylene dichloride, chloroform, ethyl acetate, acetonitrile, DMF, methyl-sulphoxide or two kinds.
3. the preparation method of amorphous tolvaptan according to claim 1, is characterized in that: described solvent II is the one in water, normal hexane, normal heptane, hexanaphthene, sherwood oil, tetrahydrofuran (THF), ether, isopropyl ether, methyl tertiary butyl ether.
4. the preparation method of amorphous tolvaptan according to claim 1, is characterized in that: the weight/volume of described tolvaptan crystal formation compound and solvent I is 1g:5～50mL.
5. the preparation method of amorphous tolvaptan according to claim 3, is characterized in that: the volume of described solvent II is 0.5～5 times of volume of solvent I.
6. the preparation method of amorphous tolvaptan according to claim 1, is characterized in that: the temperature of described cooling rear tolvaptan solution is 25～40 DEG C.
7. the preparation method of amorphous tolvaptan according to claim 1, is characterized in that: the temperature of the solvent II of described rapid stirring is 0～5 DEG C.
8. the preparation method of amorphous tolvaptan according to claim 1, is characterized in that: the time that after described interpolation completes, continuation is stirred is 5～15 minutes.
9. the preparation method of amorphous tolvaptan according to claim 1, it is characterized in that: the addition manner in described solvent II of gained tolvaptan solution being added to rapid stirring is for dripping fast or directly toppling over fast, and described time for adding or dumping time are no more than 5 minutes.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107963991A (en) * | 2017-12-29 | 2018-04-27 | 成都百裕制药股份有限公司 | A kind of production method of amorphous tolvaptan |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5258510A (en) * | 1989-10-20 | 1993-11-02 | Otsuka Pharma Co Ltd | Benzoheterocyclic compounds |
| WO2009051022A2 (en) * | 2007-10-19 | 2009-04-23 | Otsuka Pharmaceutical Co., Ltd. | Matrix-type pharmaceutical solid preparation |
| CN102020609A (en) * | 2009-09-17 | 2011-04-20 | 北京本草天源药物研究院 | Tolvapta crystal or amorphous substance and preparation method thereof |
| CN102746229A (en) * | 2005-09-02 | 2012-10-24 | 大塚制药株式会社 | Process for preparing benzazepine compounds or salts thereof |
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2014
- 2014-03-20 CN CN201410106784.6A patent/CN103880747B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5258510A (en) * | 1989-10-20 | 1993-11-02 | Otsuka Pharma Co Ltd | Benzoheterocyclic compounds |
| CN102746229A (en) * | 2005-09-02 | 2012-10-24 | 大塚制药株式会社 | Process for preparing benzazepine compounds or salts thereof |
| WO2009051022A2 (en) * | 2007-10-19 | 2009-04-23 | Otsuka Pharmaceutical Co., Ltd. | Matrix-type pharmaceutical solid preparation |
| CN102020609A (en) * | 2009-09-17 | 2011-04-20 | 北京本草天源药物研究院 | Tolvapta crystal or amorphous substance and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107963991A (en) * | 2017-12-29 | 2018-04-27 | 成都百裕制药股份有限公司 | A kind of production method of amorphous tolvaptan |
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Address after: 610000 Chengdu Wenjiang District, Sichuan Province, Chengdu Straits science and Technology Industry Development Zone Patentee after: CHENGDU BAIYU PHARMACEUTICAL CO., LTD. Address before: 610000 Chengdu Wenjiang District, Sichuan Province, Chengdu Straits science and Technology Industry Development Zone Patentee before: Chengdu Baiyu Technology Pharmaceutical Co.,Ltd. |