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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- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 title claims abstract description 41
- 229960002535 alfacalcidol Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 25
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 238000005698 Diels-Alder reaction Methods 0.000 claims abstract description 10
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 claims abstract description 6
- 239000012535 impurity Substances 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000007670 refining Methods 0.000 claims abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 235000019166 vitamin D Nutrition 0.000 claims description 16
- 239000011710 vitamin D Substances 0.000 claims description 16
- -1 tin anhydride Chemical class 0.000 claims description 5
- 238000004064 recycling Methods 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229960001866 silicon dioxide Drugs 0.000 claims description 2
- 238000007070 tosylation reaction Methods 0.000 claims description 2
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 claims 4
- 239000003999 initiator Substances 0.000 claims 2
- 239000000376 reactant Substances 0.000 claims 2
- 238000010790 dilution Methods 0.000 claims 1
- 239000012895 dilution Substances 0.000 claims 1
- 230000001590 oxidative effect Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 238000005516 engineering process Methods 0.000 abstract description 4
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 abstract description 3
- 230000007812 deficiency Effects 0.000 abstract description 2
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 abstract 1
- 235000005282 vitamin D3 Nutrition 0.000 abstract 1
- 239000011647 vitamin D3 Substances 0.000 abstract 1
- 229940021056 vitamin d3 Drugs 0.000 abstract 1
- 238000000926 separation method Methods 0.000 description 24
- 239000000243 solution Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 208000001132 Osteoporosis Diseases 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 150000002894 organic compounds Chemical class 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229940046008 vitamin d Drugs 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 206010065687 Bone loss Diseases 0.000 description 2
- 208000000038 Hypoparathyroidism Diseases 0.000 description 2
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229930003316 Vitamin D Natural products 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000005251 capillar electrophoresis Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000001292 planar chromatography Methods 0.000 description 2
- 238000003822 preparative gas chromatography Methods 0.000 description 2
- 208000007442 rickets Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 150000003710 vitamin D derivatives Chemical class 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 1
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 1
- 206010061728 Bone lesion Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000013725 Chronic Kidney Disease-Mineral and Bone disease Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- KIDXYAWWICJAFK-UHFFFAOYSA-N O.[Na].OC Chemical compound O.[Na].OC KIDXYAWWICJAFK-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 201000006409 renal osteodystrophy Diseases 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 239000004945 silicone rubber Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tert-butyl alcohol Substances CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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 (7)
| 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 |
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| 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 |
| CN117126090A (en) * | 2023-09-01 | 2023-11-28 | 正大制药（青岛）有限公司 | Impurity removal method for 5,6-trans impurities in calcitol bulk drug |
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Cited By (8)
| 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 |
| CN117126090A (en) * | 2023-09-01 | 2023-11-28 | 正大制药（青岛）有限公司 | Impurity removal method for 5,6-trans impurities in calcitol bulk drug |
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