CN102617332A - Alpha-ketovaline calcium dihydrate crystal and preparation method thereof - Google Patents
Alpha-ketovaline calcium dihydrate crystal and preparation method thereof Download PDFInfo
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- CN102617332A CN102617332A CN2012100212326A CN201210021232A CN102617332A CN 102617332 A CN102617332 A CN 102617332A CN 2012100212326 A CN2012100212326 A CN 2012100212326A CN 201210021232 A CN201210021232 A CN 201210021232A CN 102617332 A CN102617332 A CN 102617332A
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Abstract
The present invention discloses an alpha-ketovaline calcium dihydrate crystal and a preparation method thereof. In the prior art, the alpha-ketovaline calcium particles are fine, the filtration is difficult, such that the production and the separation of the alpha-ketovaline calcium particles are difficult; the alpha-ketovaline calcium has low fluidity, and the mixing difficulty is high during formulation preparation; after ketophenylalanine calcium is prepared into tablets, the solubility is low, and the stability of the alpha-ketovaline calcium is inferior to the stability of the alpha-ketovaline calcium hydrate. The present invention provides an alpha-ketovaline calcium dihydrate crystal, wherein the crystal is a dihydrate crystal of a compound represented by a chemical formula (I). According to the present invention, the alpha-ketovaline calcium dihydrate crystal of the present invention has characteristics of good stability, good solubility and dissolution rate, and provides advantages in the formulation; the bioavailability is improved; the alpha-ketovaline calcium dihydrate crystal further has characteristics of advantages in the operability of the production, easy filtration and good fluidity, and is not easy to deteriorate.
Description
Technical field
The present invention relates to α-keto-valine calcium, specifically a kind of α-keto-valine calcium dihydrate crystal and preparation method thereof.
Background technology
α-keto-valine calcium is the staple of Fu Fangα-Tong Suanpian.Fu Fangα-Tong Suanpian is used for the uremia treatment, also reduces the absorption of amino nitrogen for the nephrotic provides indispensable amino acid as far as possible.Itself does not contain amino ketone group or hydroxyamino acid, and it utilizes the nitrogen transformation of non-essential amino acid to be amino acid, therefore can reduce urea synthesis, and accumulating of uremia toxic product also is able to reduce.
The structural formula of α-keto-valine calcium is following:
（Ⅰ）
α-known compound method of keto-valine calcium has: CN101759553 obtains α-keto-valine calcium with 3-methyl-2-ketobutyric acid and calcium carbonate reaction.CN101514154 obtains the isopropylidene glycolylurea with acetone and glycolylurea reaction, uses the aqueous sodium hydroxide solution hydrolysis again, obtains α-keto-valine calcium with the calcium chloride reaction.Above α-keto-valine calcium compound method does not all relate to α-keto-valine calcium dihydrate, does not more have the description about α-keto-valine calcium dihydrate crystalline form.
α-keto-valine calcium particle is fine and smooth, and difficulty in filtration is big, gives to produce to separate and brings difficulty; α-keto-valine calcium mobile little, it is big to mix difficulty when preparation is produced; The solubleness that the ketone Phenylalanine calcium salt is processed behind the tablet is little, and the poor stability of α-keto-valine calcium is in its hydrate.
Summary of the invention
Technical problem to be solved by this invention is to overcome the defective that above-mentioned prior art exists, and a kind of α-keto-valine calcium dihydrate crystal is provided.
For this reason, the present invention adopts following technical scheme: α-keto-valine calcium dihydrate crystal, and it is the dihydrochloride dihydrate crystal with compound shown in the chemical formula I;
（Ⅰ）
, its powder x-ray diffraction spectrum of representing with 2 θ diffraction angle has diffraction peak as shown in Figure 1.
Main peaks among Fig. 1 is positioned at spacing d=16.21278, and 14.55255,13.14477,12.07106,11.15871,8.14306; 6.61066,6.24016,5.54814,4.90677,4.62479,4.4443; 4.30126,4.0206,3.89603,3.66159,3.43681,3.26564; 3.01526,2.80608,2.70558,2.51595,2.28296,2.21273; 2.13968 2.08012,2.02542,1.97745,1.89422 (unit: dust), showing more specifically will be in the table 1 or Fig. 1 of back.(the X-ray diffraction condition determination: used in cathode-ray tube Cu-K alpha-ray, tube voltage 40kv, tube current 40mA, dsin θ=n λ, n is an integer, θ is a diffraction angle).
The value of spacing d is to have high-intensity relatively peak, and it can be selected out as main peaks from X-ray peak easily, still, should be appreciated that crystalline structure is necessary to be limited by these values.That is, can comprise peak in addition, above-mentioned peak.Usually, when measuring crystal through x-ray analysis, owing to determining instrument, condition determination, adhere to existence of solvent or the like, (less) measuring error may appear in the peak.
For containing two crystal water, differential thermal is weightless about 11.68% through DTA research for α of the present invention-keto-valine calcium dihydrate, and showing more specifically will be in Fig. 2 at the back.
A kind of preparation method is following for α-keto-valine calcium dihydrate crystalline: under 0～55 ℃ of condition (preferred 10～50 ℃); α-keto-valine calcium is dissolved in the water-containing solvent; At-10～25 ℃, stir under preferred 5～25 ℃ temperature and leave standstill then, continue 1 hour to 1 day; Through filtration, centrifugal or similar approach separation, washing, dry air or drying under reduced pressure obtain α-keto-valine calcium dihydrate crystal.
The dissolution solvent of the α of 1 weight part-keto-valine calcium is 0.1～100 weight part, preferred 5～50 weight parts, more preferably 10～30 weight parts; The α of 1 weight part-keto-valine calcium, the usage quantity of water is 1～100 weight part, preferred 5～50 weight parts, more preferably 10～30 weight parts.
Described solvent is an alcohols like methyl alcohol, ethanol, propyl alcohol, Virahol, 2-methyl cellosolve, terepthaloyl moietie, methyl cellosolve, USP Kosher and Ucar 35; Ethers such as: diox, THF, glycol dimethyl ether and diethylene glycol dimethyl ether; Ketone is like acetone, methyl ethyl ketone and MIBK; The ester class is like methyl-formiate, ethyl formate, propyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, methyl propionate, ethyl propionate; Organic halogenation hydro carbons such as methylene dichloride, chloroform, tetracol phenixin, 1,2-ethylene dichloride, trichloroethane, chlorobenzene and dichlorobenzene; Nitrile is like acetonitrile and propionitrile; N; DMSO 99.8MIN.; N,N-DIMETHYLACETAMIDE; N-Methyl pyrrolidone; Quinoline; Pyridine and triethylamine.These solvents can be separately or two kinds or more kinds ofly unite use.
Drying temperature is 0～45 ℃, and preferred drying temperature is 25～35 ℃; Vacuum tightness is-0.098～0MPa (gauge pressure).
Another kind of preparation method is following for α-keto-valine calcium dihydrate crystalline: in the water that the α-keto-valine calcium reaction solution that obtains after α-keto-valine calcium midbody is reacted or its extract are dissolved in 25～55 ℃; Perhaps with water or water-containing solvent is counter adds; And under 5～25 ℃ temperature, stir and leave standstill, prepared in lasting 2-70 hour.
α of the present invention-keto-valine calcium dihydrate crystal has preferably stability and solubleness, dissolution rate, in preparation, has superiority, and has improved bioavailability; On the operability of producing, have superiority, filter easily, good fluidity, not perishable.
Below in conjunction with Figure of description and embodiment the present invention is described further.
Description of drawings
Fig. 1 is α of the present invention-keto-valine calcium dihydrate crystalline X-ray powder diffraction spectrogram.
Fig. 2 is α of the present invention-keto-valine calcium dihydrate crystalline thermogravimetric-differential thermal spectrogram.
Embodiment
Embodiment 1: the preparation of α-keto-valine calcium dihydrate
In having the 1000mL there-necked flask of mechanical stirring, TM, reflux exchanger, drop into α-keto-valine calcium 27.0g (0.1mol), add 50% methanol aqueous solution 500mL under the room temperature; Be warmed up to 50 ℃, stirring and dissolving is evaporated to muddiness (steaming 200mL approximately) under this temperature; Be cooled to 25 ℃, stirred 8 hours, filter; Filter cake filters with 100mL * 2 methyl alcohol making beating washing 2 times, and 30 ℃ of vacuum dryings are 16～20 hours under-0.090MPa.Obtain α-keto-valine calcium dihydrate 24.9g (yield 81.37%).
Moisture calculated value: 11.76%;
Ka Er-Fei Xiu (KF) moisture determination: 11.65%;
Its X-ray powder diffraction spectrum data are seen Fig. 1 and table 1, and thermogravimetric-differential thermal spectrogram is seen Fig. 2.
Table 1
| Angle | d value | Intensity |
| 2-Theta | Angstrom | Count |
| 5.447 | 16.21278 | 21 |
| 6.068 | 14.55255 | 226 |
| 6.719 | 13.14477 | 22979 |
| 7.317 | 12.07106 | 422 |
| 7.917 | 11.15871 | 86.5 |
| 10.856 | 8.14306 | 497 |
| 13.383 | 6.61066 | 37.7 |
| 14.182 | 6.24016 | 35.8 |
| 15.961 | 5.54814 | 70.8 |
| 18.064 | 4.90677 | 170 |
| 19.176 | 4.62479 | 108 |
| 19.962 | 4.4443 | 84.6 |
| 20.633 | 4.30126 | 238 |
| 22.091 | 4.0206 | 448 |
| 22.807 | 3.89603 | 21.8 |
| 24.288 | 3.66159 | 66.1 |
| 25.904 | 3.43681 | 127 |
| 27.287 | 3.26564 | 221 |
| 29.603 | 3.01526 | 106 |
| 31.866 | 2.80608 | 68.3 |
| 33.083 | 2.70558 | 200 |
| 35.657 | 2.51595 | 232 |
| 39.439 | 2.28296 | 132 |
| 40.745 | 2.21273 | 77.7 |
| 42.201 | 2.13968 | 43.6 |
| 43.47 | 2.08012 | 30.7 |
| 44.707 | 2.02542 | 13.2 |
| 45.852 | 1.97745 | 27.1 |
| 47.99 | 1.89422 | 39.1 |
Embodiment 2: the preparation of α-keto-valine calcium dihydrate
In having the 1000mL there-necked flask of mechanical stirring, TM, reflux exchanger, drop into α-keto-valine calcium 27.0g (0.1mol), add 30% methanol aqueous solution 500mL under the room temperature; Be warmed up to 50 ℃, stirring and dissolving is evaporated to muddiness (steaming 200mL approximately) under this temperature; Be cooled to 15 ℃, stirred 8 hours, filter; Filter cake filters with 100mL * 2 methyl alcohol making beating washing 2 times, and 30 ℃ of vacuum dryings are 16～20 hours under-0.090MPa.Obtain α-keto-valine calcium dihydrate 25.2g (yield 82.35%).
Moisture calculated value: 11.76%;
Ka Er-Fei Xiu (KF) moisture determination: 11.69%.
Embodiment 3: the preparation of α-keto-valine calcium dihydrate
In having the 1000mL there-necked flask of mechanical stirring, TM, reflux exchanger, drop into α-keto-valine calcium 27.0g (0.1mol), add 50% aqueous ethanolic solution 500mL under the room temperature; Be warmed up to 50 ℃, stirring and dissolving is evaporated to muddiness (steaming 200mL approximately) under this temperature; Be cooled to 5 ℃, stirred 8 hours, filter; Filter cake filters with 100mL * 2 ethanol making beating washing 2 times, and 30 ℃ of vacuum dryings are 16～20 hours under-0.090MPa.Obtain α-keto-valine calcium dihydrate 26.1g (yield 85.29%).
Moisture calculated value: 11.76%;
Ka Er-Fei Xiu (KF) moisture determination: 11.72%.
Embodiment 4: the preparation of α-keto-valine calcium dihydrate
In having the 1000mL there-necked flask of mechanical stirring, TM, reflux exchanger, drop into α-keto-valine calcium 27.0g (0.1mol), add 30% aqueous ethanolic solution 500mL under the room temperature; Be warmed up to 50 ℃, stirring and dissolving is evaporated to muddiness (steaming 200mL approximately) under this temperature; Be cooled to 25 ℃, stirred 8 hours, filter; Filter cake filters with 100mL * 2 ethanol making beating washing 2 times, and 30 ℃ of vacuum dryings are 16～20 hours under-0.090MPa.Obtain α-keto-valine calcium dihydrate 26.2g (yield 85.62%).
Moisture calculated value: 11.76%;
Ka Er-Fei Xiu (KF) moisture determination: 11.73%.
Embodiment 5: the preparation of α-keto-valine calcium dihydrate
In having the 1000mL there-necked flask of mechanical stirring, TM, reflux exchanger, drop into α-keto-valine calcium 27.0g (0.1mol), add 30% aqueous acetone solution 500mL under the room temperature; Be warmed up to 50 ℃, stirring and dissolving is evaporated to muddiness (steaming 200mL approximately) under this temperature; Be cooled to 15 ℃, stirred 8 hours, filter; Filter cake filters with 100mL * 2 acetone making beating washing 2 times, and 30 ℃ of vacuum dryings are 16～20 hours under-0.090MPa.Obtain α-keto-valine calcium dihydrate 26.7g (yield 87.25%).
Moisture calculated value: 11.76%;
Ka Er-Fei Xiu (KF) moisture determination: 11.69%.
Embodiment 6: the preparation of α-keto-valine calcium dihydrate
In having the 1000mL there-necked flask of mechanical stirring, TM, reflux exchanger, drop into α-keto-valine calcium 27.0g (0.1mol), add 20% aqueous acetone solution 500mL under the room temperature; Be warmed up to 50 ℃, stirring and dissolving is evaporated to muddiness (steaming 200mL approximately) under this temperature; Be cooled to 5 ℃, stirred 8 hours, filter; Filter cake filters with 100mL * 2 acetone making beating washing 2 times, and 30 ℃ of vacuum dryings are 16～20 hours under-0.090MPa.Obtain α-keto-valine calcium dihydrate 26.8g (yield 87.58%).
Moisture calculated value: 11.76%;
Ka Er-Fei Xiu (KF) moisture determination: 11.68%.
Claims (7)
1. α-keto-valine calcium dihydrate crystal, it is the dihydrochloride dihydrate crystal with compound shown in the chemical formula I;
?
（Ⅰ）
, its powder x-ray diffraction spectrum of representing with 2 θ diffraction angle has diffraction peak as shown in Figure 1.
2. the described α of claim 1-keto-valine calcium dihydrate crystalline preparation method; Its step is following: under 0～55 ℃ of condition; α-keto-valine calcium is dissolved in the water-containing solvent; Under-10～25 ℃, stir and leave standstill then, continue 1 hour to 1 day, obtain α-keto-valine calcium dihydrate crystal through separation, washing and drying.
3. α according to claim 2-keto-valine calcium dihydrate crystalline preparation method is characterized in that, the α of 1 weight part-keto-valine calcium, and the usage quantity of solvent is 0.1～100 weight part, the usage quantity of water is 1～100 weight part.
4. α according to claim 3-keto-valine calcium dihydrate crystalline preparation method is characterized in that the usage quantity of solvent is 5～50 weight parts, and the usage quantity of water is 5～50 weight parts.
5. α according to claim 4-keto-valine calcium dihydrate crystalline preparation method is characterized in that the usage quantity of solvent is 10～30 weight parts, and the usage quantity of water is 10～30 weight parts.
6. α according to claim 2-keto-valine calcium dihydrate crystalline preparation method; It is characterized in that; Described solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, 2-methyl cellosolve, terepthaloyl moietie, methyl cellosolve, USP Kosher, Ucar 35 、 diox, THF, glycol dimethyl ether, diethylene glycol dimethyl ether, acetone, methyl ethyl ketone, MIBK, methyl-formiate, ethyl formate, propyl formate, methyl acetate, ETHYLE ACETATE, propyl acetate, butylacetate, methyl propionate, ethyl propionate, methylene dichloride, chloroform, tetracol phenixin, 1, a kind of or mixture more than two kinds in 2-ethylene dichloride, trichloroethane, chlorobenzene, dichlorobenzene, acetonitrile, propionitrile, N, DMSO 99.8MIN., N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone, quinoline, pyridine, the triethylamine.
7. the described α of claim 1-keto-valine calcium dihydrate crystalline preparation method; Its step is following: in the water that the α-keto-valine calcium reaction solution that obtains after α-keto-valine calcium midbody is reacted or its extract are dissolved in 25～55 ℃; Perhaps with water or aqueous solvent is counter adds; And under 5～25 ℃ temperature, stir and leave standstill, prepared in lasting 2-70 hour.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104607410A (en) * | 2014-12-23 | 2015-05-13 | 上海景峰制药有限公司 | Method for washing compound alpha-ketoacid tablet particles left on oven tray or oven screen |
| CN106316828A (en) * | 2016-08-16 | 2017-01-11 | 浙江新和成股份有限公司 | Preparation method of alpha-keto-isoleucine-calcium dihydrate and alpha-keto-valine-calcium dihydrate |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101991570A (en) * | 2009-08-14 | 2011-03-30 | 上海秀新臣邦医药科技有限公司 | Stable compound keto acid preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101991570A (en) * | 2009-08-14 | 2011-03-30 | 上海秀新臣邦医药科技有限公司 | Stable compound keto acid preparation and preparation method thereof |
Non-Patent Citations (7)
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| 《中国优秀博硕士学位论文全文数据库(硕士)工程科技I辑》 20061231 丁威 《海因法合成几种alpha-酮酸及alpha-酮酸盐》 , 第4期 * |
| 《精细化工中间体》 20111231 郝宏山等 alpha-酮缬氨酸钙合成工艺研究 第41卷, 第01期 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104607410A (en) * | 2014-12-23 | 2015-05-13 | 上海景峰制药有限公司 | Method for washing compound alpha-ketoacid tablet particles left on oven tray or oven screen |
| CN106316828A (en) * | 2016-08-16 | 2017-01-11 | 浙江新和成股份有限公司 | Preparation method of alpha-keto-isoleucine-calcium dihydrate and alpha-keto-valine-calcium dihydrate |
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