CN103880747B - The preparation method of amorphous tolvaptan - Google Patents
The preparation method of amorphous tolvaptan Download PDFInfo
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- CN103880747B CN103880747B CN201410106784.6A CN201410106784A CN103880747B CN 103880747 B CN103880747 B CN 103880747B CN 201410106784 A CN201410106784 A CN 201410106784A CN 103880747 B CN103880747 B CN 103880747B
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- 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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Abstract
The invention discloses a kind of preparation method of amorphous tolvaptan, tolvaptan crystal-form compound to be dissolved in solvent I and to be cooled to 25 ~ 40 DEG C, the weight/volume of tolvaptan crystal-form compound and solvent I is 1g:5 ~ 50mL, then gained tolvaptan solution is added in the solvent II of rapid stirring, solid is had to separate out in adding procedure, the consumption of described solvent II is 0.5 ~ 5 times of described solvent I, the temperature keeping the solvent II of rapid stirring is 0 ~ 5 DEG C, add rear continuation stirring 5 ~ 15 minutes, then filter, drying obtains amorphous tolvaptan.The present invention is by using different solvents respectively in dissolution phase and precipitation phase, control solvent temperature change and consumption, make amorphous tolvaptan output higher, and preparation method of the present invention is simple, easy handling, need not the main equipments such as fluidized-bed be used, more positive effect can be played to the popularization of this medicine.
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 developed by Japanese great Zhong drugmaker, within 2009, go on the market at US and European respectively, trade(brand)name: SAMSCA, is mainly used in the hyponatremia for the treatment of the not enough syndrome patient of heart failure, liver cirrhosis and antidiuretic hormone secretion.
Tolvaptan chemical name: N-[4-[(5RS)-7-chloro-5-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-form compound, drug quality and clinical efficacy can be improved significantly, therefore study its amorphous products and have great importance.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 mentions its preparation method, amorphous composite is formed by the weight ratio of tolvaptan and hydroxypropylcellulose 1: 1 is dissolved in the mixed solvent spraying dry of methylene dichloride and lower alcohol, but need to use the main equipments such as fluidized-bed in this preparation process, be unfavorable for preparation and the popularization of product; And in Chinese patent application CN102020609, also depict the method for making of unformed tolvaptan, 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
Instant invention overcomes the deficiencies in the prior art, the embodiment of a kind of preparation method of amorphous tolvaptan is provided, prepare amorphous tolvaptan with more economical more succinct method, make 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-form compound to be dissolved in solvent I to obtain tolvaptan solution, after cooling, described tolvaptan solution is added in the solvent II of rapid stirring, solid is had to separate out in adding procedure, continue to be stirred to precipitation solid after having added no longer to increase, then filtration, drying obtain amorphous tolvaptan.
Solvent I can effectively dissolve tolvaptan crystal-form compound, and solvent II can allow the tolvaptan be dissolved in solvent I separate out fast, thus reaches the object of the amorphous tolvaptan of preparation fast.
Further technical scheme is: described solvent I is methyl alcohol, the mixing solutions of a kind of in 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-form compound and solvent I is 1g:5 ~ 50mL.
Further technical scheme is: the volume of described solvent II is 0.5 ~ 5 times of the volume of solvent I.
Further technical scheme is: after described cooling, the temperature of 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 of continuing after described interpolation completes to stir is 5 ~ 15 minutes.
Further technical scheme is: described is fast drop or direct rapid dumps by the addition manner that gained tolvaptan solution adds in the solvent II of rapid stirring, 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 different solvents respectively in dissolution phase and precipitation phase, control solvent temperature change and consumption, amorphous tolvaptan output is made to reach while 85 ~ 95%, its preparation method is simpler, and easy handling, need not use the main equipments such as fluidized-bed, and the unformed tolvaptan with high clinical value can be prepared fast, more positive effect can be played to the popularization of this medicine.
Accompanying drawing explanation
Fig. 1 is the XRD figure of tolvaptan crystal-form compound of the present invention.
Fig. 2 is the XRD data sheet of Fig. 1.
Fig. 3 is the DSC figure of tolvaptan crystal-form compound of the present invention.
Fig. 4 is the TGA figure of tolvaptan crystal-form 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 clearly understand, 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, be not intended to limit the present invention.
The present invention is with tolvaptan crystal-form compound for amorphous tolvaptan prepared by starting material, and tolvaptan crystal-form compound can be prepared by following method:
1120mL methylene dichloride and 4560mL ethanol is added in 10L reaction flask, the chloro-1-of 800g7-[2-methyl-4-(2-methylbenzoylamin. o) benzoyl]-2 is added under stirring, 3, 4, 5-tetrahydro-1 H-1-benzazepino-5-ketone, reactant suspends and stirs, control temperature is 15 ~ 25 DEG C, point multiple batches of slowly add 57.6g POTASSIUM BOROHYDRIDE, control temperature is 20 ~ 25 DEG C and stirs 5 hours, drip the aqueous hydrochloric acid 2500mL termination reaction of 0.5%, mixture is allowed to stir 1 hour at 20 ~ 25 DEG C, cool maintenance 0 ~ 5 DEG C subsequently to stir 4 hours, filtering solids, 50 ~ 60 DEG C of drying under reduced pressure are to constant weight, obtain tolvaptan crystal-form compound 717g, as the tolvaptan crystal-form compound raw material 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)。
Embodiment 1
In 2L reaction flask, add 1500mL acetone, 50g tolvaptan crystal-form compound, heated and stirred to dissolving completely, obtains acetone-tolvaptan solution, naturally cool under stirring 25 DEG C for subsequent use.
The normal hexane (temperature is 2 DEG C) that 6000mL cools in advance is added in 10L reaction flask, under rapid stirring, in 5 minutes, to normal hexane fast drop above-mentioned acetone-tolvaptan solution, separate out a large amount of solid at once, after dropwising, continue stirring 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%.
Embodiment 2
In 1L reaction flask, add 500mL methyl alcohol, 50g tolvaptan crystal-form compound, heated and stirred to dissolving completely, obtains methyl alcohol-tolvaptan solution, naturally cool under stirring 35 DEG C for subsequent use.
The water (temperature is 5 DEG C) that 1500mL cools in advance is added in 3L reaction flask, under rapid stirring, pour into above-mentioned tolvaptan solution, separate out a large amount of solid at once, after toppling over, continue stirring 5 minutes, filter, 50 DEG C of drying under reduced pressure are to constant weight, and obtain the amorphous tolvaptan of 45.8g, productive rate reaches 91.6%.
Embodiment 3
In 2L reaction flask, add 800mL ethanol, 50g tolvaptan crystal-form compound, heated and stirred to dissolving completely, obtains ethanol-tolvaptan solution, naturally cool under stirring 40 DEG C for subsequent use.
The water (temperature is 4 DEG C) that 2000mL cools in advance is added in 5L reaction flask, under rapid stirring, in 5 minutes, fast drop enters above-mentioned ethanol-tolvaptan solution, separates out a large amount of solid at once, after dropwising, continue stirring 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%.
Embodiment 4
In 3L reaction flask, add 1500mL ethyl acetate, 300mL methylene dichloride, 50g tolvaptan crystal-form compound, heated and stirred to dissolving completely, obtains mixing solutions, naturally cool under stirring 30 DEG C for subsequent use.
In 10L reaction flask, add the sherwood oil (temperature is 0 DEG C) that 5400mL cools in advance, under rapid stirring, pour into above-mentioned mixing solutions, separate out a large amount of solid at once, continue stirring 10 minutes, filter, 50 DEG C of drying under reduced pressure are to constant weight, and obtain the amorphous tolvaptan of 48.6g, productive rate reaches 97.2%.
Embodiment 5
In 2L reaction flask, add 750mL ethyl acetate, 250mL DMF, 50g tolvaptan crystal-form compound, heated and stirred to dissolving completely, obtains mixing solutions, naturally cool under stirring 25 DEG C for subsequent use.
The sherwood oil (temperature is 5 DEG C) that 5000mL cools in advance is added in 10L reaction flask, under rapid stirring, pour into above-mentioned tolvaptan solution, separate out a large amount of solid at once, continue stirring 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-form compound, heated and stirred to dissolving completely, naturally cool under stirring 30 DEG C for subsequent use.
In 3L reaction flask, add the water (temperature is 1 DEG C) that 125mL cools in advance, under rapid stirring, pour into above-mentioned tolvaptan solution, separate out a large amount of solid at once, continue stirring 5 minutes, filter, 60 DEG C of drying under reduced pressure are to constant weight, and obtain the amorphous tolvaptan of 45.6g, productive rate reaches 91.2%.
Embodiment 7
In 3L reaction flask, add 2500mL Virahol, 50g tolvaptan crystal-form compound, heated and stirred to dissolving completely, obtains Virahol-tolvaptan solution, naturally cool under stirring 40 DEG C for subsequent use.
The tetrahydrofuran (THF) (temperature is 3 DEG C) that 1250mL cools in advance is added in 5L reaction flask, under rapid stirring, pour into above-mentioned Virahol-tolvaptan solution, separate out a large amount of solid at once, continue stirring 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%.
Embodiment 8
In 2L reaction flask, add 1000mL chloroform, 250mL methyl alcohol, 50g tolvaptan crystal-form compound, heated and stirred to dissolving completely, obtains mixing solutions, naturally cool under stirring 35 DEG C for subsequent use.
The methyl tertiary butyl ether (temperature is 5 DEG C) that 1250mL cools in advance is added in 5L reaction flask, under rapid stirring, pour into above-mentioned tolvaptan solution, separate out a large amount of solid at once, continue stirring 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 dissolve tolvaptan crystal-form compound with the mixture of the solvent I used in ethanol or ethanol and embodiment 1 ~ 8, can also replace the solvent II used 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 ~ 4 are crystal formation tolvaptan XRD, DSC, TGA collection of illustrative plates used in the present invention, and wherein Fig. 2 is the data list of Fig. 1; Fig. 5 ~ 7 are XRD, DSC, TGA collection of illustrative plates of unformed tolvaptan prepared by the present invention.
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 embodiment, these amendments and embodiment will drop within spirit disclosed in the present application and spirit.More particularly, in the scope of, accompanying drawing open in the application and claim, multiple modification and improvement can be carried out to the building block of subject combination layout and/or layout.Except the modification of carrying out building block and/or layout is with except improvement, to those skilled in the art, other purposes also will be obvious.
Claims (7)
1. the preparation method of an amorphous tolvaptan, it is characterized in that: comprise the steps: tolvaptan crystal-form compound to be dissolved in solvent I to obtain tolvaptan solution, after cooling, described tolvaptan solution is added in the solvent II of rapid stirring, solid is had to separate out in adding procedure, continue to be stirred to precipitation solid after having added no longer to increase, then filtration, drying obtain amorphous tolvaptan; 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; Described solvent II is the one in water, normal hexane, normal heptane, hexanaphthene, sherwood oil, tetrahydrofuran (THF), ether, isopropyl ether, methyl tertiary butyl ether.
2. the preparation method of amorphous tolvaptan according to claim 1, is characterized in that: the weight/volume of described tolvaptan crystal-form compound and solvent I is 1g:5 ~ 50mL.
3. the preparation method of amorphous tolvaptan according to claim 1, is characterized in that: the volume of described solvent II is 0.5 ~ 5 times of the volume of solvent I.
4. the preparation method of amorphous tolvaptan according to claim 1, is characterized in that: after described cooling, the temperature of tolvaptan solution is 25 ~ 40 DEG C.
5. 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.
6. the preparation method of amorphous tolvaptan according to claim 1, is characterized in that: the time of continuing after described interpolation completes to stir is 5 ~ 15 minutes.
7. the preparation method of amorphous tolvaptan according to claim 1, it is characterized in that: described is fast drop or direct rapid dumps by the addition manner that gained tolvaptan solution adds in the solvent II of rapid stirring, and described time for adding or dumping time are no more than 5 minutes.
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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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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 |
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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. |