CN105254548A - Doxercalciferol purification method - Google Patents
Doxercalciferol purification method Download PDFInfo
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- CN105254548A CN105254548A CN201510725401.8A CN201510725401A CN105254548A CN 105254548 A CN105254548 A CN 105254548A CN 201510725401 A CN201510725401 A CN 201510725401A CN 105254548 A CN105254548 A CN 105254548A
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- doxercalciferol
- acetone
- hexanaphthene
- middle product
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Abstract
The invention provides a doxercalciferol purification method, which comprises the following steps of 1, recrystallizing doxercalciferol coarse products and cyclohexane to obtain a first intermediate product; 2, recrystallizing the first intermediate product and acetone to obtain a second intermediate product; 3, recrystallizing the second intermediate product and cyclohexane mixed solvents to obtain a third intermediate product; 4, recrystallizing the third intermediate product, the acetone, the cyclohexane and the ethanol mixed solvents to obtain high-purity doxercalciferol. The method has the advantages that the doxercalciferol coarse products are subjected to four times of recrystallization, and the high-purity doxercalciferol finished product with the single purity content being less than 0.1 percent and the total impurity content being less than 0.5 percent can be prepared and obtained.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of purification process of development of drugs in treating primary osteoporosis doxercalciferol.
Background technology
Vitamins D class clinical drug is mainly used in treat osteoporosis, key agents has calcitriol, alfacalcidol, doxercalciferol etc., and wherein doxercalciferol is free from side effects to the hemodialysis patients with Secondary Hyperparathyroidism and is widely used.Doxercalciferol can not only promote that Calcium and phosphorous absorption treats osteoporosis, also has the effect such as inducing apoptosis of tumour cell, inhibition tumor cell transfer.
There is no highly purified doxercalciferol bulk drug in the market to sell, the product that the purification process reported obtains has a common deficiency, and namely the purity of product is lower, and multiple list is assorted more than 0.1%, total assorted more than 1%, all do not reach national drug standards of the application.
In view of this, be necessary to be improved the purification process of doxercalciferol in prior art, to solve the problem.
Summary of the invention
The object of the invention is to the purification process of openly a kind of doxercalciferol, in order to reduce the foreign matter content in doxercalciferol.
For achieving the above object, the invention provides a kind of purification process of doxercalciferol, comprise the following steps:
Step (1): doxercalciferol crude product and hexanaphthene recrystallization are obtained the first middle product;
Step (2): the first middle product and acetone recrystallization are obtained the second middle product;
Step (3): the second middle product and acetone, hexanaphthene mixed solvent recrystallization are obtained the 3rd middle product;
Step (4): the 3rd middle product and acetone, hexanaphthene, alcohol mixed solvent recrystallization are obtained highly purified doxercalciferol.
In certain embodiments, the doxercalciferol crude product in step (1) and the weight ratio of hexanaphthene are 1:1-1:100.
In certain embodiments, in step (1), the weight ratio of doxercalciferol crude product and hexanaphthene is 1:1-1:12.
In certain embodiments, step (1) to the recrystallization temperature in step (4) is that room temperature is to reflux temperature.
In certain embodiments, step (1) is reflux temperature to the recrystallization temperature in step (4).
In certain embodiments, in step (2), the weight ratio of the first middle product and acetone is 1:1-1:50.
In certain embodiments, in step (3), the weight ratio of the second middle product and acetone, hexanaphthene is 1:1:1-1:10:100.
In certain embodiments, in step (4), the weight ratio of the 3rd middle product and acetone, hexanaphthene, ethanol is 1:1:10:50-1:50:100:0.5.
In certain embodiments, in step (4), the weight ratio of the 3rd middle product and acetone, hexanaphthene, ethanol is 1:25:11:0.5.
Compared with prior art, the invention has the beneficial effects as follows: in the present invention, by doxercalciferol crude product successively with hexanaphthene, acetone, acetone and hexanaphthene mixed solvent, acetone and hexanaphthene and ethanol through four recrystallizations, thus single foreign matter content can be prepared be less than 0.1%, the highly purified doxercalciferol finished product that total impurities is less than 0.5%.
Accompanying drawing explanation
Fig. 1 is the high-efficient liquid phase chromatogram of the doxercalciferol in embodiment one after purifying;
Fig. 2 is the high-efficient liquid phase chromatogram of the doxercalciferol in embodiment two after purifying.
Embodiment
Below in conjunction with each embodiment, the present invention is described in detail; but should be noted that; these embodiments are not limitation of the present invention; those of ordinary skill in the art are according to these embodiment institute work energy, method or structural equivalent transformations or substitute, and all belong within protection scope of the present invention.If no special instructions, the room temperature in each embodiment of this specification sheets is specially 23 DEG C; " h " is specially time measurement unit: hour; " min " is specially time measurement unit: minute; " ml " is specially volume unit: milliliter; " L " is specially volume unit: rise.
embodiment one:
Step (1): add 25g doxercalciferol crude product (80% purity) in 500ml flask, add hexanaphthene 300ml again, magnetic stirring apparatus carries out magnetic agitation, add reflux after mixing, after reflow treatment 15min, color clarification, continues reflow treatment 1h, stop heating, naturally be down to room temperature, stirring and crystallizing 3h, in Suction filtration device, carry out suction filtration process to obtain filter cake.Under filter cake is placed in the environment of 35 DEG C, dry 8h in vacuum unit, obtained the first middle product 21g in white powder.
Step (2): the first middle product adding 21g previous step gained doxercalciferol in 1L flask, add acetone 672ml again, magnetic stirring apparatus carries out magnetic agitation, be added to reflux after mixing, after reflow treatment 10min, color clarification, continues reflow treatment 1h, stop heating, naturally be down to room temperature, stirring and crystallizing 3h, carry out suction filtration process to obtain filter cake in Suction filtration device.Under filter cake is placed in the environment of 35 DEG C, dry 8h in vacuum unit, obtains the second middle product 17g of white powder.
Step (3): the second middle product adding 17g previous step gained doxercalciferol in 1L flask, add 85ml hexanaphthene and 255ml acetone again, magnetic agitation on magnetic stirring apparatus, reflux is added after mixing, color clarification after reflow treatment 2min, continue reflow treatment, stop heating, naturally room temperature is down to, stirring and crystallizing 3h, carries out suction filtration process to obtain filter cake, under filter cake is placed in the environment of 35 DEG C in Suction filtration device, dry 8h in vacuum unit, obtains the 3rd middle product 12.2g of white powder.
Step (4): add gained doxercalciferol crude product in 12.2g previous step in 1L flask, add 305ml acetone, 134ml hexanaphthene and 5.6ml ethanol again, magnetic agitation on magnetic stirring apparatus, reflux is added after mixing, color clarification after reflow treatment 2min, continue backflow 2.5h, stop heating, naturally room temperature is down to, stirring and crystallizing 5h, carries out suction filtration process to obtain filter cake, under filter cake is placed in the environment of 35 DEG C in Suction filtration device, dry 8h in vacuum unit, obtains the highly purified doxercalciferol crystal 8.8g of white powder.In the present embodiment, single foreign matter content of the doxercalciferol finished product of final results is 0.08%, and total impurities is less than 0.45%.
Detected by HPLC, obtain the high-efficient liquid phase chromatogram of the doxercalciferol shown in Fig. 1.
The chromatographic condition that HPLC detects: analytical column: CapcellC18MG (2.0mm × 50mm, 5 μm); Post pressure: 50 ~ 90 × 105Pa; Moving phase: A pump 5mmolL
-1ammonium acetate aqueous solution, B pump acetonitrile; Flow velocity: 0.25mLmin
– 1; Gradient: 0 ~ 0.1min, 30% ~ 100%B; 0.1 ~ 1.5min, 100%B; 1.5 ~ 1.6min, 100% ~ 30%B; 1.6 ~ 5min, 30%B.End time: 5min; Sample size: 20 μ L or 5 μ L.
In the present embodiment, the physical constant of the purified doxercalciferol obtained is as follows:
UV:δmax＝265nm，δmax＝211nm；1HNMR(400MHZ,CHCl3)：6.35(1H,d)，6.07(1H,d)，5.34(1H,s)，5.02(1H,s)，4.39(1H,m)，4.23(1H,m)，2.72(1H,m)，2.58(1H,m)，2.37(1H,m，0.98(3H,d)，0.85(6H,m)。m/z：400[M]+。
embodiment two:
Step (1): add 25g doxercalciferol crude product (80% purity) in 500ml flask, add hexanaphthene 500ml again, magnetic stirring apparatus carries out magnetic agitation, add reflux after mixing, after reflow treatment 15min, color clarification, continues reflow treatment 1h, stop heating, naturally be down to room temperature, stirring and crystallizing 3h, in Suction filtration device, carry out suction filtration process to obtain filter cake.Under filter cake is placed in the environment of 35 DEG C, dry 8h in vacuum unit, obtained the first middle product 22.4g in white powder.
Step (2): the first middle product adding 22.4g previous step gained doxercalciferol in 2L flask, add acetone 1100ml again, magnetic stirring apparatus carries out magnetic agitation, be added to reflux after mixing, after reflow treatment 10min, color clarification, continues reflow treatment 1h, stop heating, naturally be down to room temperature, stirring and crystallizing 3h, carry out suction filtration process to obtain filter cake in Suction filtration device.Under filter cake is placed in the environment of 35 DEG C, dry 8h in vacuum unit, obtains the second middle product 20.75g of white powder.
Step (3): the second middle product adding 20.75g previous step gained doxercalciferol in 1L flask, add 150ml hexanaphthene and 750ml acetone again, magnetic agitation on magnetic stirring apparatus, reflux is added after mixing, color clarification after reflow treatment 2min, continue reflow treatment, stop heating, naturally room temperature is down to, stirring and crystallizing 3h, carries out suction filtration process to obtain filter cake, under filter cake is placed in the environment of 35 DEG C in Suction filtration device, dry 8h in vacuum unit, obtains the 3rd middle product 14.51g of white powder.
Step (4): add gained doxercalciferol crude product in 14.51g previous step in 4L flask, add 650ml acetone, 1300ml hexanaphthene and 5.6ml ethanol again, magnetic agitation on magnetic stirring apparatus, reflux is added after mixing, color clarification after reflow treatment 2min, continue backflow 2.5h, stop heating, naturally room temperature is down to, stirring and crystallizing 5h, carries out suction filtration process to obtain filter cake, under filter cake is placed in the environment of 35 DEG C in Suction filtration device, dry 8h in vacuum unit, obtains the highly purified doxercalciferol crystal 10.7g of white powder.In the present embodiment, single foreign matter content of the doxercalciferol finished product of final results is 0.075%, and total impurities is less than 0.48%.
Detected by HPLC, obtain the high-efficient liquid phase chromatogram of the doxercalciferol shown in Fig. 2.
The chromatographic condition that HPLC detects: analytical column: CapcellC18MG (2.0mm × 50mm, 5 μm); Post pressure: 50 ~ 90 × 105Pa; Moving phase: A pump 5mmolL
-1ammonium acetate aqueous solution, B pump acetonitrile; Flow velocity: 0.25mLmin
– 1; Gradient: 0 ~ 0.1min, 30% ~ 100%B; 0.1 ~ 1.5min, 100%B; 1.5 ~ 1.6min, 100% ~ 30%B; 1.6 ~ 5min, 30%B.End time: 5min; Sample size: 20 μ L or 5 μ L.
In the present embodiment, the physical constant of the purified doxercalciferol obtained is as follows:
UV:δmax＝265nm，δmax＝211nm；1HNMR(400MHZ,CHCl3)：6.35(1H,d)，6.15(1H,d)，5.30(1H,s)，5.12(1H,s)，4.36(1H,m)，4.19(1H,m)，2.69(1H,m)，2.55(1H,m)，2.31(1H,m，0.98(3H,d)，0.85(6H,m)。m/z：400[M]+。
A series of detailed description listed is above only illustrating for feasibility embodiment of the present invention; they are also not used to limit the scope of the invention, all do not depart from the skill of the present invention equivalent implementations done of spirit or change all should be included within protection scope of the present invention.
Claims (9)
1. a purification process for doxercalciferol, is characterized in that, comprises the following steps:
Step (1): doxercalciferol crude product and hexanaphthene recrystallization are obtained the first middle product;
Step (2): the first middle product and acetone recrystallization are obtained the second middle product;
Step (3): the second middle product and acetone, hexanaphthene mixed solvent recrystallization are obtained the 3rd middle product;
Step (4): the 3rd middle product and acetone, hexanaphthene, alcohol mixed solvent recrystallization are obtained highly purified doxercalciferol.
2. the purification process of doxercalciferol according to claim 1, is characterized in that, the doxercalciferol crude product in described step (1) and the weight ratio of hexanaphthene are 1:1-1:100.
3. the purification process of doxercalciferol according to claim 1, is characterized in that, in described step (1), the weight ratio of doxercalciferol crude product and hexanaphthene is 1:1-1:12.
4. the purification process of doxercalciferol according to claim 1, is characterized in that, described step (1) to the recrystallization temperature in step (4) is that room temperature is to reflux temperature.
5. the purification process of doxercalciferol according to claim 4, is characterized in that, described step (1) is reflux temperature to the recrystallization temperature in step (4).
6. the purification process of doxercalciferol according to claim 1, is characterized in that, in described step (2), the weight ratio of the first middle product and acetone is 1:1-1:50.
7. the purification process of doxercalciferol according to claim 1, is characterized in that, in described step (3), the weight ratio of the second middle product and acetone, hexanaphthene is 1:1:1-1:10:100.
8. the purification process of doxercalciferol according to claim 1, is characterized in that, in described step (4), the weight ratio of the 3rd middle product and acetone, hexanaphthene, ethanol is 1:1:10:50-1:50:100:0.5.
9. the purification process of doxercalciferol according to claim 8, is characterized in that, in described step (4), the weight ratio of the 3rd middle product and acetone, hexanaphthene, ethanol is 1:25:11:0.5.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237452A (en) * | 2015-11-01 | 2016-01-13 | 南京海融制药有限公司 | Novel crystalline form of doxercalciferol and preparation method for novel crystalline form |
| CN116023313A (en) * | 2022-12-27 | 2023-04-28 | 南京海鲸药业股份有限公司 | Docalcitol compound crystal and capsule thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863809A (en) * | 2010-05-12 | 2010-10-20 | 重庆泰濠制药有限公司 | Method for purifying doxercalciferol |
| US20120108554A1 (en) * | 2010-10-28 | 2012-05-03 | Formosa Laboratories, Inc. | PROCESS FOR PREPARING HIGH PURITY 1alpha-HYDROXY VITAMIN D2 |
| CN103588689A (en) * | 2012-08-17 | 2014-02-19 | 台耀化学股份有限公司 | Crystalline form of maxacalcitol |
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2015
- 2015-10-29 CN CN201510725401.8A patent/CN105254548A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863809A (en) * | 2010-05-12 | 2010-10-20 | 重庆泰濠制药有限公司 | Method for purifying doxercalciferol |
| US20120108554A1 (en) * | 2010-10-28 | 2012-05-03 | Formosa Laboratories, Inc. | PROCESS FOR PREPARING HIGH PURITY 1alpha-HYDROXY VITAMIN D2 |
| CN103588689A (en) * | 2012-08-17 | 2014-02-19 | 台耀化学股份有限公司 | Crystalline form of maxacalcitol |
Non-Patent Citations (1)
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| 孙博等: "度骨化醇的合成", 《中国新药杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105237452A (en) * | 2015-11-01 | 2016-01-13 | 南京海融制药有限公司 | Novel crystalline form of doxercalciferol and preparation method for novel crystalline form |
| CN116023313A (en) * | 2022-12-27 | 2023-04-28 | 南京海鲸药业股份有限公司 | Docalcitol compound crystal and capsule thereof |
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Application publication date: 20160120 |