CN103073469A - Preparation method for alfacalcidol - Google Patents
Preparation method for alfacalcidol Download PDFInfo
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- CN103073469A CN103073469A CN201310014976XA CN201310014976A CN103073469A CN 103073469 A CN103073469 A CN 103073469A CN 201310014976X A CN201310014976X A CN 201310014976XA CN 201310014976 A CN201310014976 A CN 201310014976A CN 103073469 A CN103073469 A CN 103073469A
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Abstract
The invention relates to a preparation method for a compound, in particular to the preparation method for separating and purifying alfacalcidol. Aiming at the deficiencies of the conventional preparation technology, the invention provides a novel method for preparing alfacalcidol with good yield and high purity. The preparation method comprises the steps as follows: taking vitamin D3 as a raw material; removing most of trans-isomer impurities generated after chemical reaction by utilizing Diels-Alder reaction; and refining and purifying by preparative high pressure liquid chromatography to prepare high-purity alfacalcidol. According to the preparation method, the reaction conditions are moderate, the yield is high, and the purity of alfacalcidol reaches up to 99.5%.
Description
Technical field
The present invention relates to a kind of preparation method of compound, particularly the preparation method of the separation and purification of alfacalcidol belongs to the synthetic field of medicine.(organic compound synthesis technical field)
Background technology
Alfacalcidol, chemical name: 9,10-open loop courage steroid-5Z, 7E, 10(19)-triolefin-1a, the 3b-glycol.Chemical formula is:
Alfacalcidol is the fat-soluble sterol in the vitamin d compounds, is the material that a class participates in the mineralisation process of the homeostasis of calcium, phosphorus and bone.Alfacalcidol is vitamins D
3The activated vitamin D that comes through 1 α of kidney-hydroxylase role transformation in vivo.
Alfacalcidol has treatment postmenopausal women and person in middle and old age's property osteoporosis, hypoparathyroidism, vitamins D
3Effect (the Kanis JA such as the kidney source property rickets that dependency rickets, renal osteodystrophy and being used for caused by multiple nephropathys such as renal failures, kidney bone lesion, hypoparathyroidism, Kidney International, 1999, V.56 Suppl 73, S77-81., Hauselmann HJ, Rizzoli R, Osteoporosis international, 14,2-12).In addition, alfacalcidol is to secondary osteoporosis, and especially the treatment of the bone loss of the adrenocortical steroid osteoporosis of inducing and organ transplantation postoperative plays an important role.And then alfacalcidol is found significantly to reduce insecondary bone-loss behind heart, lung and the hepatic transplantation recently.
Alfacalcidol character is unstable, and is all very sensitive to light, heat, air, especially produces easily a trans-isomer(ide) in reaction process, is difficult to separation and purification, thereby the difficult assurance of synthesis condition, and the synthesis technology threshold is high, difficulty is large.The synthetic method of alfacalcidol, document have been reported several method (Paaren HE, Deluca HF, schnoes HK.Direct C (1) Hydroxylation of Vitamin D
3And Related Compounds [J] .Org Chem 1980,45 (16): 3253-3258; DeLuca, Method for preparing 1a-Hydroxyvitamin D compounds. US 4554106. 1985.11.19).The described method of document is not quite similar, but all exists yield low, the separation and purification hard problem.
According to the character of alfacalcidol, separation method commonly used has vapor-phase chromatography and liquid phase chromatography.Vapor-phase chromatography has the advantage that separation efficiency is high, highly sensitive, analysis speed is fast, but is not suitable for analyzing the compound of high boiling point organic compound, polymer and poor heat stability, and alfacalcidol is to thermally labile, so be not suitable for using this method.Liquid phase chromatography is divided again capillary electrophoresis, planar chromatography and column chromatography.The capillary electrophoresis good separating effect, separating obtained thing is clean, pollutions is little and cost is low, but its passage is thin, and sample separation is few, and alfacalcidol do not have obvious positive and negative electrode, so also be not suitable for the alfacalcidol separation.Tlc is fit to the alfacalcidol separation in the planar chromatography, tlc has the advantage that applied sample amount is large, disengaging time is lacked, and its instrument is simple, easy to operate, sample pretreatment is simple, but inferior separating effect, error is large, steric isomer is inseparable, and the recycling step after separating is numerous and diverse, and the sample loss amount is large in its process.Column chromatography is commonly used medium pressure liquid chromatography method and high performance liquid chromatography, and the medium pressure liquid chromatography method is relatively simple, and applied sample amount is large; But its inferior separating effect, chromatographic column can only fill the column operation complexity with once, and disengaging time is long, and is difficult to solve the separation of complex mixture.High pressure lipuid chromatography (HPLC) be applicable to high boiling point not volatile, be subjected to the organic compound that thermally labile is labile, molecular weight is large; It is highly sensitive, so separation efficiency is high, velocity of separation is fast, and is not subjected to the restriction of volatility and the thermostability of sample, can separate at ambient temperature, do not need high column temperature, sample is not destroyed through after the chromatographic column, can collect one-component, separation and purification is effective, sample purity is high after separating, but also Reusability of chromatographic column, the trouble of having removed the dress post from; Its shortcoming is that the sample separation amount is little, so the production cycle is long, and uses multi-solvents as moving phase, separation costs is higher, easily cause again environmental pollution, be not suitable for large production (Yu Shilin. colleges and universities' liquid-phase chromatography method and application. Beijing: Chemical Industry Press, 2000).
In sum, all there is certain limitation in existing separation method, makes turnout low, and the cycle is long, and yield is low, and is difficult to effectively obtain the alfacalcidol sterling, should design one more reasonable, cost is low, meets the preparation method of suitability for industrialized production.Among the present invention with vitamins D
3Be bulk drug, get highly purified alfacalcidol by chemical separation (Diels-Alder reaction) with the method that physical sepn (HPLC separation and purification) combines.
Summary of the invention
The objective of the invention is the deficiency for existing technology of preparing, provide a kind of productive rate good, the novel method of the preparation alfacalcidol that product purity is higher.The present invention gets highly purified alfacalcidol by chemical separation (Diels-Alder reaction) with the method that physical sepn (HPLC separation and purification) combines.
The present invention implements by the following method: with vitamins D
3Be raw material, utilize the Diels-Alder reaction to remove the trans-isomer(ide) impurity that generates behind most of chemical reaction, namely get highly purified alfacalcidol finally by preparation type high pressure liquid chromatography purifying.
Concrete steps are as follows: vitamins D
3Through tosylation, pass ring, oxidation, open loop; impurity---the trans-isomer(ide) that generate behind most of chemical reaction main also is the most difficult separation is removed in recycling Diels-Alder reaction, namely gets alfacalcidol finally by preparation type high pressure liquid chromatography purifying.
This process route chart is as follows:
Beneficial effect of the present invention is:
The inventive method is selected rationally, creatively utilizes method that chemical separation (Diels-Alder reaction) combines with physical sepn (HPLC separation and purification) and must highly purified alfacalcidol.Method is simple, can effectively remove impurity, thorough separation of stereoisomers, and gained alfacalcidol purity is up to 99.5%, and productive rate can reach 40.0%.Avoided yield low, problems such as high cost, and greatly shortened the production cycle are applicable to industry and amplify, and application prospect is arranged, and save time for the separation and preparation of chipal compounds provides referential, economic, efficient preparation method.
Embodiment
⑴ vitamins D
3Synthesizing of p-toluenesulfonic esters (2a)
With vitamins D
310g and tosic acid acyl chlorides 14g add in the reaction flask together, and with 100mL pyridine dissolve complete, mixing is placed on and places 48h in the refrigerator (2～4 ℃); Add 20g ice cube and 100mL saturated sodium bicarbonate solution, stir 15min with the Tosyl chloride of decomposing excessive; With the 1500mL ethyl acetate extraction; Organic layer is respectively with 3% dilute hydrochloric acid (500mL * 2), and then saturated sodium bicarbonate solution (500mL * 1) and saturated nacl aqueous solution (500 mL * 1) washing with the anhydrous magnesium sulfate dehydration, filter; Filtrate decompression is concentrated into dried, and getting light yellow solid is crude product VD
3P-toluenesulfonic esters 13.5g, yield 97.0%, this crude product can be directly used in the next step.
⑵ 3,5-cyclization vitamins D
3Synthesizing (3a)
Add 13.0g compound 2a, sodium bicarbonate 35g and methyl alcohol 2500mL in the there-necked flask of 3000 mL, 55 ℃ are stirred 8h; Reclaim under reduced pressure methyl alcohol is used the 1500mL ethyl acetate extraction; The ester layer is washed to neutrality, with the anhydrous magnesium sulfate dehydration, filters, and filtrate decompression is concentrated into dried, gets i.e. 3, the 5-cyclization vitamins D of light yellow oil
39.4g, yield 97.5%, this crude product can be directly used in the next step.
⑶ 1a-OH-3,5-cyclization vitamins D
3Synthesizing (4a)
In the there-necked flask of 3000mL, add 9.3g compound 3a, tin anhydride 0.26g and methylene dichloride 2500mL, stirring at room 30min.To the dichloromethane solution 50mL that wherein drips 10% tertbutanol peroxide, rate of addition is 0.5ml/min; After dropwising, restir 20 minutes; Reaction solution is successively with 10% sodium hydroxide solution (200mL), water (400mL * 2) washing, and organic layer dewaters with anhydrous magnesium sulfate, filters, and filtrate decompression is concentrated into dried yellow oil 9.5g; Column chromatography ［ column layer chromatography silicone rubber, ethyl acetate-sherwood oil (60-90 ℃) is eluent (1:10) ］ separating-purifying, getting light yellow oil behind the concentrating under reduced pressure is 1a-OH-3,5-cyclization VD
3Sterling 5.8g, yield 60.0%.
⑷ 1a-OH vitamins D
3Synthesizing of (alfacalcidol)
Add 5.8g compound 4a and Glacial acetic acid 120mL in the there-necked flask of 250mL, 55 ℃ are stirred 15min, are evaporated to dried, with the 100mL anhydrous alcohol solution, to wherein adding 2.0 g maleic anhydrides, 40 ℃ are stirred 8h, to the sodium hydrate methanol solution 50mL that wherein adds 10%, stirred 3 hours again; Reaction solution is with the 1500mL ethyl acetate extraction, organic layer be washed to neutral after with the anhydrous magnesium sulfate dehydration, filter, be evaporated to dried light yellow solid 4.64g, be the alfacalcidol crude product.
This building-up process has merged three important chemical reactions in fact dexterously, has saved last handling process, has improved whole preparation efficiency.Its reaction mechanism is as follows:
1. open loop-1a-OH vitamins D
3Synthesizing of-3-acetic ester (5a)
2. Diels-Alder reacts-removes trans-isomer(ide) impurity 5b
3. hydrolysis-1a-OH vitamins D
3Synthesizing of (alfacalcidol)
⑸ high pressure liquid chromatography purifying alfacalcidol
With the 200ml dissolve with methanol, millipore filtration (0.45 μ m) filters, and carries out purifying with preparation type high pressure liquid chromatography with the 4th alfacalcidol crude product 4.64g that goes on foot the reaction gained; Chromatographic column be silicagel column (10 μ, 40 ' 250mm), the detection wavelength is 265nm, moving phase is methyl alcohol: sherwood oil (30-60 ℃) (1:6), flow velocity is 50ml/min; Sample size is 1ml, collects alfacalcidol peak component; Be evaporated to do and namely get highly purified alfacalcidol 4.0g; Detect by analysis, the purity of alfacalcidol reaches 99.5%.
Claims (8)
1. the preparation method of an alfacalcidol is characterized in that with vitamins D
3Be raw material, through tosylation, pass ring, oxidation, open loop, the trans-isomer(ide) impurity that generates behind most of chemical reaction is removed in recycling Diels-Alder reaction, namely gets highly purified alfacalcidol finally by the refining purifying of preparation type high pressure liquid chromatography.
2. oxidizing reaction according to claim 1, it is characterized in that: the consumption of strictly controlling reaction initiator tin anhydride and oxygenant tertbutyl peroxide, the optimum mole ratio of initiator tin anhydride and reactant is 1:10, and the optimum mole ratio of oxygenant tertbutyl peroxide and reactant is 1.5:1; And the mode that the oxygenant tertbutyl peroxide adopts dilution to drip.
3. method according to claim 1 and 2, the best weaker concn of oxygenant tertbutyl peroxide is 10%-20%, best rate of addition is decided according to weaker concn, requires to drip off at 90-100 minute.
4. Diels-Alder reaction according to claim 1, it is characterized in that: selected reactive material is to sterically hindered extremely sensitive maleic anhydride in the Diels-Alder reaction.
5. the method for high pressure liquid chromatography purifying alfacalcidol according to claim 1, it is characterized in that: the ratio of high pressure liquid chromatography mobile phase methanol and sherwood oil (30-60 ℃) is 1:3～1:10, and flow velocity is 20ml/min～100ml/min.
6. method according to claim 1 or 5, the more preferred proportional range of high pressure liquid chromatography mobile phase methanol and sherwood oil (30-60 ℃) is 1:5～1:8, flow velocity is 40ml/min～60ml/min.
7. the method for high pressure liquid chromatography purifying alfacalcidol according to claim 1, it is characterized in that: the high pressure liquid chromatography post is silicagel column (10 μ, 40 * 250mm).
8. the method for high pressure liquid chromatography purifying alfacalcidol according to claim 1 is characterized in that: it is 265nm that high pressure liquid chromatography detects wavelength.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047108A (en) * | 2017-12-30 | 2018-05-18 | 南京海融制药有限公司 | A kind of relative substance PZB of Alfacalcidol and its preparation method and application |
| CN109206350A (en) * | 2017-06-29 | 2019-01-15 | 江苏汉邦科技有限公司 | A method of Alfacalcidol is purified using supercritical fluid chromatography |
| CN109503445A (en) * | 2018-12-21 | 2019-03-22 | 江苏卓和药业有限公司 | A kind of Alfacalcidol class compound and preparation method thereof |
| CN109516939A (en) * | 2018-12-21 | 2019-03-26 | 江苏卓和药业有限公司 | A kind of refining methd of Alfacalcidol |
| CN111072540A (en) * | 2019-12-26 | 2020-04-28 | 山东华铂凯盛生物科技有限公司 | Improved alfacalcidol preparation method |
| CN114671792A (en) * | 2022-04-24 | 2022-06-28 | 杭州下沙生物科技有限公司 | Method for preparing 1 alpha-calciferol |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4554106A (en) * | 1984-11-01 | 1985-11-19 | Wisconsin Alumni Research Foundation | Method for preparing 1α-hydroxyvitamin D compounds |
| CN1709869A (en) * | 2005-05-31 | 2005-12-21 | 台州市海盛化工有限公司 | Vitamin D separating, purifying and crystallizing method |
| CN101223135A (en) * | 2005-07-18 | 2008-07-16 | 特瓦制药工业有限公司 | Preparation of paricalcitol and crystalline forms thereof |
| JP2009013154A (en) * | 2006-09-29 | 2009-01-22 | Teijin Pharma Ltd | 2-substituted 14-epi-previtamin d3 derivative |
-
2013
- 2013-01-16 CN CN201310014976XA patent/CN103073469A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4554106A (en) * | 1984-11-01 | 1985-11-19 | Wisconsin Alumni Research Foundation | Method for preparing 1α-hydroxyvitamin D compounds |
| CN1709869A (en) * | 2005-05-31 | 2005-12-21 | 台州市海盛化工有限公司 | Vitamin D separating, purifying and crystallizing method |
| CN101223135A (en) * | 2005-07-18 | 2008-07-16 | 特瓦制药工业有限公司 | Preparation of paricalcitol and crystalline forms thereof |
| JP2009013154A (en) * | 2006-09-29 | 2009-01-22 | Teijin Pharma Ltd | 2-substituted 14-epi-previtamin d3 derivative |
Non-Patent Citations (1)
| Title |
|---|
| 陈阳生等: "阿法骨化醇合成的新方法", 《中国新药杂志》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109206350A (en) * | 2017-06-29 | 2019-01-15 | 江苏汉邦科技有限公司 | A method of Alfacalcidol is purified using supercritical fluid chromatography |
| CN108047108A (en) * | 2017-12-30 | 2018-05-18 | 南京海融制药有限公司 | A kind of relative substance PZB of Alfacalcidol and its preparation method and application |
| CN109503445A (en) * | 2018-12-21 | 2019-03-22 | 江苏卓和药业有限公司 | A kind of Alfacalcidol class compound and preparation method thereof |
| CN109516939A (en) * | 2018-12-21 | 2019-03-26 | 江苏卓和药业有限公司 | A kind of refining methd of Alfacalcidol |
| CN111072540A (en) * | 2019-12-26 | 2020-04-28 | 山东华铂凯盛生物科技有限公司 | Improved alfacalcidol preparation method |
| CN114671792A (en) * | 2022-04-24 | 2022-06-28 | 杭州下沙生物科技有限公司 | Method for preparing 1 alpha-calciferol |
| CN114671792B (en) * | 2022-04-24 | 2024-04-26 | 杭州下沙生物科技有限公司 | Method for preparing 1 alpha-calcitol |
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Application publication date: 20130501 |