CN102643302A - Preparation method of synthetic intermediate of 25-hydroxyvitamin D2and 1α, 25-dihydroxyvitamin D2 - Google Patents
Preparation method of synthetic intermediate of 25-hydroxyvitamin D2and 1α, 25-dihydroxyvitamin D2 Download PDFInfo
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- CN102643302A CN102643302A CN201210098034XA CN201210098034A CN102643302A CN 102643302 A CN102643302 A CN 102643302A CN 201210098034X A CN201210098034X A CN 201210098034XA CN 201210098034 A CN201210098034 A CN 201210098034A CN 102643302 A CN102643302 A CN 102643302A
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Abstract
The invention discloses a method for preparing intermediates for 25-hydroxyvitamin D2 and 1 alpha, 25-dihydroxyvitamin D2. The structures of the intermediates are compounds 2 and 3 shown as the following formula 1. The preparation method is shown as the following formulas, and comprises the following steps of: treating a phosphorus oxide 9 by using strong base, and performing a Wittig-Hormer reaction with aldehyde 5 or 6. Formula 1.
Description
Technical field
The present invention relates to the preparation method of two kinds of organic cpds, say it is 25-hydroxy-vitamin D definitely
2With 1 α, the 25-dihydroxyvitamin D
2The preparation method.
Background technology
Formula 1
Suc as formula the 25-hydroxy-vitamin D shown in 1
2With 1 α, the 25-dihydroxyvitamin D
2, all be the regulator of calcium phosphorus running balance in animal and human's body
1,2Their activity in cell recognition have also been found in nearest research
3,4,5Therefore; Various types of 25-hydroxy-vitamin D analogues have caused investigator's extensive interest; The for example analogue of the verivate of vitamins D side chain, different hydroxyl models, the analogue of different steric configurations, etc., all be widely used in polytype active testing; A plurality of known these compounds have all been showed good active in external body, shown that effect good in multiple disease treatment and potential should
1Hafner，V.；Rutsch，C.；Ding，R.；Heinrich，T.；Diedrichs，L.；Schmidt-Gayk，H.；Walter-Sack，I.；Bommer，J.；Mikus，G.Int.J.Clin.Pharm.Therap.2008，46(3)，131-135.
2Nakane，Masaki；Ma，Junli；Rose，Andrew?E.；Osinski，Mark?A.；Wu-Wong，J.Ruth.J.?Steroid?Biochem.Mol.Biology?2007，103(1)，84-89
3Coyne，D.W.；Grieff，M.；Ahya，S.N.；Giles，K.；Norwood，K.；Slatopolsky，E.Am.J.Kidney?Diseases2002，40(6)，1283-1288
4Slatopolsky，E.；Cozzolino，M.；Finch，J.L.Kidney?International?2002，62(4)，1277-1284.
5Rown, A.J.; Finch, J.; Slatopolsky, E.J.Lab.Clin.Med.2002,139 (5), 279-284. is with being worth, like the rickets of the dysplasia of treatment sclerotin, anti-vitamins D
6, osteoporosis
7, vitamin D deficiency such as psoriasis
8Simultaneously, the 25-hydroxy vitamin has become its functional attributes that detects nutritional status.
According to bibliographical information, 25-hydroxy-vitamin D
2With 1 α, the 25-dihydroxyvitamin D
2Mainly be through synthesizing as shown in the formula the midbody shown in 22 and 3; Promptly; The protection base that compound 3 is directly sloughed on the hydroxyl obtains compound 1a or 1b; The two keys of illumination counter-rotating obtained 1a or 1b after perhaps compound 2 was sloughed the protection base on the hydroxyl, and wherein compound 3 can be obtained through the two keys of illumination counter-rotating by compound 2.
Formula 2
Compound 2 and 3 mainly are through the corresponding aldehyde 5 of compound and 6 and following side chain compound 7 or 8 synthetic through Wittig reaction, Julia coupling olefination or Wiitig-Horner reaction.Wherein, Julia coupling olefination mainly uses suc as formula the compound shown in 37 as the side chain fragment, and the Wittig reaction is then used suc as formula the compound shown in 38 as side chain fragment (patent documentation US4847012, US5260290 etc.).Wherein, compound 7 is being used for compound 1a and 1b and their analogue when synthetic, and yield is very low, and will construct through the desulfurization alkylene of coupling and Na-Hg through two-step reaction, and operation is inconvenient, dirt
6Puschett?J.B.；Genel?M.；Rastegar?A.；Anast?C.；DeLuca?H.F.；Friedman?A.Clin.pharm.Thera.1975，17(2)，202-11.
7Balint，E.；Marshall，C.F.；Sprague，S.M.Am.J.Kidney?Diseases?2000，36(4)，789-796.
8Petkovich, P.M; Helvig, C.F.; Melnick, J.Z.PCT Int.Appl.2009,61pp.WO2009124210. dyes greatly.Compound 8 not only be used for medicine when synthetic yield low, and the synthetic and purifying of compound 3 itself are difficult to, its building-up process also causes some limitations for the basic R of protection functional group.Therefore, seeking new side chain compound replaces compound 2 and compound 8 preparation compound 1a and 1b to have crucial meaning.
Formula 3
Summary of the invention
The present invention provides a kind of new method Synthetic 2 5-hydroxy-vitamine D
2With 1 α, the 25-dihydroxyvitamin D
2, its adopt structure suc as formula compound shown in 49 as the side chain source, the precursor compound 2 and 3 the concrete synthetic reaction formula that react synthetic compound 1a and 1b through compound 9 and aldehyde 5 and 6 Wittig-Horner are following:
Formula 4
Wherein, R is the straight chain alkoxyl group of phenyl or tolyl or phenoxy or carbonatoms no more than ten, R
1Be tertiary butyl dimethyl Si base or triethyl siloxy or trimethylsiloxy group or tert-butyl diphenyl siloxy or methoxy methoxy base or benzyloxy methoxyl group or 2-tetrahydro-pyran oxy or 2-tetrahydrofuran oxygen base or benzoyloxy, R
2Silica-based or triethyl is silica-based or trimethyl silicon based or tert-butyl diphenyl is silica-based or methoxyl methyl or benzyloxymethyl or 2-THP trtrahydropyranyl or 2-tetrahydrofuran base or benzoyl-, R for tertiary butyl dimethyl-
3For Wasserstoffatoms or triethyl is silica-based or trimethyl silicon based or methoxyl methyl or benzyloxymethyl or 2-THP trtrahydropyranyl or 2-tetrahydrofuran base or benzoyl-.
With compound 5 or 6 and compound 9 reaction constructs compound 2 and 3 usefulness is that Wittig-Horner reacts.After we handle compound 9 usefulness highly basic fourth positive group lithiums or tert-butyl lithium or secondary butyllithium or diisopropylamine lithium or potassium tert.-butoxide or sodium hydride or hexamethl disilamine base lithium or hexamethl disilamine base potassium or hexamethl disilamine base sodium or lithium methide or phenyl lithium; With compound 5 or 6 reactions, obtain compound 2 or 3 again.
Compound 2 and 3 just can obtain medicine and divide 1a and 1b after removing the two keys of protection base, counter-rotating of hydroxyl through document US 4847012, US5260290 method.On the hydroxyl of compound 2 or 3,, can handle compound 6 with tosic acid or hydrochloric acid or Hydrogen bromide or sulfuric acid or methylsulfonic acid or tosic acid pyridinium salt and can obtain compound 1a or 1b with tertiary butyl dimethyl Si base or triethyl siloxy or trimethylsiloxy group or tert-butyl diphenyl siloxy or methoxy methoxy base or benzyloxy methoxyl group or 2-tetrahydro-pyran oxy or 2-tetrahydrofuran oxygen base.If can remove the protection base with acyl group with the Lithium Aluminium Hydride reduction or with sodium alkoxide or lithium alkoxide or potassium alcoholate or the such alkaline condition of salt of wormwood as when base protection on the hydroxyl of compound 1a and 1b.
Because with respect to compound 7 and 8; The compound 9 of patent CN201110231702.7 report is synthetic easier; Product is more stable and be easy to purifying, therefore comes synthetic compound 1a and 1b just to have higher feasibility than existing method with compound 9 as side chain, experiment confirm provided by the present invention suc as formula the compound shown in 45 or 6 and the method for compound 9 prepared in reaction compounds 2 and 3 not only yield height, route are brief; And product is easy to purifying, and quality product is better.
Embodiment
Embodiment one: the preparation method of compound 2a-1,2b-1 and 3a-1 and 3b-1.Wherein R is a phenyl, R
2For tertiary butyl dimethyl-silica-based, R
3For trimethyl silicon based; R among 2a-1 and the 3a-1
1Be Wasserstoffatoms, R among 2b-1 and the 3b-1
1Be methoxymethoxy, its reaction formula difference is (formula 5) as follows:
Formula 5
Getting 600mg compound 9-1 is dissolved in the 10mL anhydrous tetrahydro furan; Be cooled to subzero 78 degrees centigrade under the nitrogen protection; Then to the tetrahydrofuran solution that wherein slowly splashes into the butyllithium of 1.0mL 1.6mol/L; Drip off back intensification naturally and continued stirring reaction 30 minutes, below-40 degrees centigrade 500mg 5a-1 tetrahydrofuran solution is slowly being splashed into wherein then, continue stirring reaction 2h.Naturally rise to room temperature, the saturated ammonium chloride cancellation, ethyl acetate extraction, organic phase concentrates behind anhydrous sodium sulfate drying, and the resistates silica gel column chromatography obtains 0.45g 2a-1 respectively.
Same method, 600mg 5b-1 obtains 560mg 2b-1 through same reaction, and 500mg 6a-1 then reacts the 3a-1 that obtains 480mg, and 600mg 6b-1 reaction obtains 570mg 3b-1.
Embodiment two: the preparation method of compound 2a-2,2b-2 and 3a-2 and 3b-2.Wherein R is a p-methylphenyl, R
2Be methoxyl methyl, R
3Be the 2-THP trtrahydropyranyl; R among 2a-2 and the 3a-2
1Be Wasserstoffatoms, R among 2b-2 and the 3b-2
1Be the triethyl siloxy, its reaction formula difference is (formula 6) as follows:
Formula 6
Getting 800mg compound 9-2 is dissolved in the 10mL anhydrous tetrahydro furan; Be cooled to subzero 78 degrees centigrade under the nitrogen protection; Then to the tetrahydrofuran solution that wherein slowly splashes into the tert-butyl lithium of 2.5mL 1.0mol/L; Drip off back intensification naturally and continued stirring reaction 30 minutes, below-70 degrees centigrade the 640mg5a-2 tetrahydrofuran solution is slowly being splashed into wherein then, continue stirring reaction 2h.Naturally rise to room temperature, the saturated ammonium chloride cancellation, ethyl acetate extraction, organic phase concentrates behind anhydrous sodium sulfate drying, and the resistates silica gel column chromatography obtains 0.62g 2a-2 respectively.
Same method, 700mg 5b-2 obtains 600mg 2b-2 through same reaction, and 640mg 6a-2 reaction obtains the 3a-2 of 580mg, and 720mg 6b-2 reaction obtains 60mg 3b-2.
Embodiment three: the preparation method of compound 2a-3,2b-3 and 3a-3 and 3b-3.Wherein R is a methoxyl group, R
2Be 2-tetrahydrofuran base, R
3Be methoxyl methyl; R among 2a-3 and the 3a-3
1Be Wasserstoffatoms, R among 2b-3 and the 3b-3
1Be benzoyloxy, its reaction formula difference is (formula 7) as follows:
Formula 7
Getting the 100mg sodium hydride joins in the 10mL anhydrous n-hexane; Be cooled to zero degrees celsius under the nitrogen protection; Then to the hexane solution that wherein slowly drips compound 800mg compound 9-3; Drip off back intensification naturally and continued stirring reaction 30 minutes, at 0 degree centigrade 700mg 5a-3 hexane solution is slowly splashed into wherein then, continue stirring reaction 5h.Naturally rise to room temperature, add shrend and go out, ethyl acetate extraction, organic phase concentrates behind anhydrous sodium sulfate drying, and the resistates silica gel column chromatography obtains 0.60g 2a-3 respectively.
Same method, 700mg 5b-3 obtains 550mg 2b-3 through same reaction, and 680mg 6a-3 reaction obtains the 3a-3 of 580mg, and 720mg 6b-3 reaction obtains 560mg 3b-3.
Embodiment four: the preparation method of compound 2a-4,2b-4 and 3a-4 and 3b-4.Wherein R is an oxygen base in the last of the ten Heavenly stems, R
2Be benzoyl-, R
3For triethyl silica-based; R among 2a-4 and the 3a-4
1Be Wasserstoffatoms, R among 2b-4 and the 3b-4
1Be 2-tetrahydrofuran oxygen base, its reaction formula difference is (formula 8) as follows:
Formula 8
Getting the 220mg potassium tert.-butoxide joins in the 20mL dry toluene; Be cooled to zero degrees celsius under the nitrogen protection; Then to the toluene solution that wherein slowly drips compound 700mg compound 9-4; Drip off back intensification naturally and continued stirring reaction 30 minutes, at 0 degree centigrade 580mg 5a-4 toluene solution is slowly splashed into wherein then, continue stirring reaction 5h.Naturally rise to room temperature, add shrend and go out, ethyl acetate extraction, organic phase concentrates behind anhydrous sodium sulfate drying, and the resistates silica gel column chromatography obtains 0.48g 2a-4 respectively.
Same method, 650mg 5b-4 obtains 400mg 2b-4 through same reaction, and 680mg 6a-4 reaction obtains the 3a-4 of 480mg, and 700mg 6b-4 reaction obtains 460mg 3b-4.
Embodiment five: the preparation method of compound 2a-5,2b-5 and 3a-5 and 3b-5.Wherein R is a butoxy, R
2Be benzyloxymethyl, R
3Be benzoyl-; R among 2a-5 and the 3a-5
1Be Wasserstoffatoms, R among 2b-5 and the 3b-5
1Be the tert-butyl diphenyl siloxy, its reaction formula difference is (formula 9) as follows:
Formula 9
Getting 600mg compound 9-5 is dissolved in the 10mL anhydrous tetrahydro furan; Be cooled to subzero 78 degrees centigrade under the nitrogen protection; Then to the tetrahydrofuran solution of the lithium diisopropyl amido of the 1mL 2.0mol/L that wherein slowly splashes into new system; Drip off back intensification naturally and continued stirring reaction 30 minutes, below-40 degrees centigrade 600mg 5a-5 tetrahydrofuran solution is slowly being splashed into wherein then, continue stirring reaction 2h.Naturally rise to room temperature, the saturated ammonium chloride cancellation, ethyl acetate extraction, organic phase concentrates behind anhydrous sodium sulfate drying, and the resistates silica gel column chromatography obtains 620mg 2a-5 respectively.
Same method, 620mg 5b-5 obtains 660mg 2b-5 through same reaction, and 500mg6a-5 then reacts the 3a-5 that obtains 530mg, and 600mg 6b-5 reaction obtains 570mg 3b-5.
Embodiment six: the preparation method of compound 2a-6,2b-6 and 3a-6 and 3b-6.Wherein R is a phenoxy, R
2For triethyl silica-based, R
3Be benzyloxymethyl; R among 2a-6 and the 3a-6
1Be Wasserstoffatoms, R among 2b-6 and the 3b-6
1Be the benzyloxy methoxyl group, its reaction formula difference is (formula 10) as follows:
Formula 10
Getting 600mg compound 9-6 is dissolved in the 10mL anhydrous diethyl ether; Be cooled to subzero 78 degrees centigrade under the nitrogen protection; Then to the toluene solution that wherein slowly splashes into 2mL1.0mol/L hexamethl disilamine base potassium; Drip off back intensification naturally and continued stirring reaction 30 minutes, below-40 degrees centigrade 520mg 5a-6 diethyl ether solution is slowly being splashed into wherein then, continue stirring reaction 2h.Naturally rise to room temperature, the saturated ammonium chloride cancellation, ethyl acetate extraction, organic phase concentrates behind anhydrous sodium sulfate drying, and the resistates silica gel column chromatography obtains 420mg 2a-6 respectively.
Same method, 620mg 5b-6 obtains 500mg 2b-6 through same reaction, and 500mg 6a-6 then reacts the 3a-6 that obtains 410mg, and 600mg 6b-6 reaction obtains 510mg 3b-6.
Embodiment seven: the preparation method of compound 2a-7,2b-7 and 3a-7 and 3b-7.Wherein R is an o-tolyl, R
2Be benzyloxymethyl, R
3Be benzoyl-; R among 2a-7 and the 3a-7
1Be Wasserstoffatoms, R among 2b-7 and the 3b-7
1Be the 2-tetrahydro-pyran oxy, its reaction formula difference is (formula 11) as follows:
Getting 200mg compound 9-7 is dissolved in the 10mL anhydrous diethyl ether; Be cooled to subzero 78 degrees centigrade under the nitrogen protection; Then to the hexane solution that wherein slowly splashes into 0.7mL1.0mol/L hexamethl disilamine base lithium; Drip off back intensification naturally and continued stirring reaction 30 minutes, below-40 degrees centigrade 200mg 5a-7 diethyl ether solution is slowly being splashed into wherein then, continue stirring reaction 1h.Naturally rise to room temperature, the saturated ammonium chloride cancellation, ethyl acetate extraction, organic phase concentrates behind anhydrous sodium sulfate drying, and the resistates silica gel column chromatography obtains 120mg 2a-7 respectively.
Formula 11
Same method, 220mg 5b-7 obtains 150mg 2b-7 through same reaction, and 200mg 6a-7 then reacts the 3a-7 that obtains 110mg, and 200mg 6b-7 reaction obtains 110mg 3b-7.
Embodiment eight: the preparation method of compound 2a-8,2b-8 and 3a-8 and 3b-8.Wherein R is an oxyethyl group, R
2Be 2-THP trtrahydropyranyl, R
3Be the 2-tetrahydrofuran base; R among 2a-7 and the 3a-7
1Be Wasserstoffatoms, R among 2b-8 and the 3b-8
1Be the tertiary butyl dimethyl Si base, its reaction formula difference is (formula 12) as follows:
Getting 1g compound 9-8 is dissolved in the 30mL anhydrous tetrahydro furan; Be cooled to subzero 78 degrees centigrade under the nitrogen protection; Then to the tetrahydrofuran solution that wherein slowly splashes into the 2mL1.5mol/L phenyl lithium; Drip off back intensification naturally and continued stirring reaction 30 minutes, 1.2g 5a-8 diethyl ether solution is slowly splashed into wherein below 40 degrees centigrade subzero then, continue stirring reaction 1h.Naturally rise to room temperature, the saturated ammonium chloride cancellation, ethyl acetate extraction, organic phase concentrates behind anhydrous sodium sulfate drying, and the resistates silica gel column chromatography obtains 700mg2a-8 respectively.
Formula 12
Same method, 1g 5b-8 obtains 650mg 2b-8 through same reaction, and 1.2g 6a-8 then reacts the 3a-8 that obtains 610mg, and 1.2g 6b-8 reaction obtains 710mg 3b-8.
Embodiment nine: the preparation method of compound 2a-9,2b-9 and 3a-9 and 3b-9.Wherein R is a n-octyloxy, R
2For trimethyl silicon based, R
3Be Wasserstoffatoms; R among 2a-9 and the 3a-9
1Be Wasserstoffatoms, R among 2b-7 and the 3b-7
1Be trimethylsiloxy group, its reaction formula difference is (formula 13) as follows:
Getting 1.15g compound 9-9 is dissolved in the 30mL anhydrous n-hexane; Be cooled to subzero 78 degrees centigrade under the nitrogen protection; Then to the hexane solution that wherein slowly splashes into lithium methide; Drip off back intensification naturally and continued stirring reaction 30 minutes, below-40 degrees centigrade 500mg 5a-9 diethyl ether solution is slowly being splashed into wherein then, continue stirring reaction 1h.Naturally rise to room temperature, the saturated ammonium chloride cancellation, ethyl acetate extraction, organic phase concentrates behind anhydrous sodium sulfate drying, and the resistates silica gel column chromatography obtains 320mg 2a-9 respectively.
Same method, 420mg 5b-9 obtains 250mg 2b-9 through same reaction, and 600mg 6a-9 then reacts the 3a-9 that obtains 410mg, and 500mg 6b-9 reaction obtains 210mg 3b-9.
Formula 13
Claims (2)
1. as shown in the formula the Synthetic 2 5-hydroxy-vitamine D shown in 4
2With 1 α, the 25-dihydroxyvitamin D
2The preparation method of midbody compound 2, after it is characterized in that earlier phosphorus oxidation compound 9 usefulness highly basic being handled, with aldehyde 5 the Wittig-Hormer reaction takes place again and obtains compound 2,
Formula 4
Wherein, R is the straight chain alkoxyl group of phenyl or tolyl or phenoxy or carbonatoms no more than ten; R
1Be tertiary butyl dimethyl Si base or triethyl siloxy or trimethylsiloxy group or tert-butyl diphenyl siloxy or methoxy methoxy base or benzyloxy methoxyl group or 2-tetrahydro-pyran oxy or 2-tetrahydrofuran oxygen base or benzoyloxy; R
2Silica-based or triethyl is silica-based or trimethyl silicon based or tert-butyl diphenyl is silica-based or methoxyl methyl or benzyloxymethyl or 2-THP trtrahydropyranyl or 2-tetrahydrofuran base or benzoyl-for tertiary butyl dimethyl-; R
3For Wasserstoffatoms or triethyl is silica-based or trimethyl silicon based or methoxyl methyl or benzyloxymethyl or 2-THP trtrahydropyranyl or 2-tetrahydrofuran base or benzoyl-; Highly basic is n-Butyl Lithium or tert-butyl lithium or secondary butyllithium or diisopropylamine lithium or potassium tert.-butoxide or sodium hydride or hexamethl disilamine base lithium or hexamethl disilamine base potassium or hexamethl disilamine base sodium or lithium methide or phenyl lithium.
2. as shown in the formula the Synthetic 2 5-hydroxy-vitamine D shown in 1
2With 1 α, the 25-dihydroxyvitamin D
2The preparation method of midbody compound 3, after it is characterized in that earlier phosphorus oxidation compound 9 usefulness highly basic being handled, with aldehyde 6 the Wittig-Hormer reaction takes place again and obtains compound 3,
Formula 1
Wherein, R is the straight chain alkoxyl group of phenyl or tolyl or phenoxy or carbonatoms no more than ten; R
1Be tertiary butyl dimethyl Si base or triethyl siloxy or trimethylsiloxy group or tert-butyl diphenyl siloxy or methoxy methoxy base or benzyloxy methoxyl group or 2-tetrahydro-pyran oxy or 2-tetrahydrofuran oxygen base or benzoyloxy; R
2Silica-based or triethyl is silica-based or trimethyl silicon based or tert-butyl diphenyl is silica-based or methoxyl methyl or benzyloxymethyl or 2-THP trtrahydropyranyl or 2-tetrahydrofuran base or benzoyl-for tertiary butyl dimethyl-; R
3For Wasserstoffatoms or triethyl is silica-based or trimethyl silicon based or methoxyl methyl or benzyloxymethyl or 2-THP trtrahydropyranyl or 2-tetrahydrofuran base or benzoyl-; Highly basic is n-Butyl Lithium or tert-butyl lithium or secondary butyllithium or diisopropylamine lithium or potassium tert.-butoxide or sodium hydride or hexamethl disilamine base lithium or hexamethl disilamine base potassium or hexamethl disilamine base sodium or lithium methide or phenyl lithium.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106008302A (en) * | 2016-06-16 | 2016-10-12 | 无锡贝塔医药科技有限公司 | Preparation method of vitamin D2 derivative |
| JP2017508790A (en) * | 2014-03-07 | 2017-03-30 | ▲凱▼菜英医▲薬▼集▲団▼（天津）股▲フン▼有限公司 | Intermediate compound for producing rosuvastatin calcium and method for producing rosuvastatin calcium using the same |
| CN110272367A (en) * | 2019-05-13 | 2019-09-24 | 无锡贝塔医药科技有限公司 | The preparation method of the calciferol internal standard compound of label |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017508790A (en) * | 2014-03-07 | 2017-03-30 | ▲凱▼菜英医▲薬▼集▲団▼（天津）股▲フン▼有限公司 | Intermediate compound for producing rosuvastatin calcium and method for producing rosuvastatin calcium using the same |
| US9926283B2 (en) | 2014-03-07 | 2018-03-27 | Asymchem Laboratories (Tianjin) Co., Ltd. | Intermediate compound for preparing rosuvastatin calcium and method for preparing rosuvastatin calcium therefrom |
| CN106008302A (en) * | 2016-06-16 | 2016-10-12 | 无锡贝塔医药科技有限公司 | Preparation method of vitamin D2 derivative |
| CN106008302B (en) * | 2016-06-16 | 2018-08-07 | 无锡贝塔医药科技有限公司 | A kind of vitamin D2The preparation method of derivative |
| CN110272367A (en) * | 2019-05-13 | 2019-09-24 | 无锡贝塔医药科技有限公司 | The preparation method of the calciferol internal standard compound of label |
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Application publication date: 20120822 |