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EP0000073A1 - 24-Dehydrovitamin D3 Derivate und Verfahren zu ihrer Herstellung und diese enthaltende Präparate - Google Patents

24-Dehydrovitamin D3 Derivate und Verfahren zu ihrer Herstellung und diese enthaltende Präparate Download PDF

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Publication number
EP0000073A1
EP0000073A1 EP78100144A EP78100144A EP0000073A1 EP 0000073 A1 EP0000073 A1 EP 0000073A1 EP 78100144 A EP78100144 A EP 78100144A EP 78100144 A EP78100144 A EP 78100144A EP 0000073 A1 EP0000073 A1 EP 0000073A1
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EP
European Patent Office
Prior art keywords
dehydro
hydroxy
mixture
dehydrovitamin
desoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP78100144A
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English (en)
French (fr)
Inventor
Howard Jones
Shu Shu Yang
Conrad Peter Dorn, Jr.
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of EP0000073A1 publication Critical patent/EP0000073A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0036—Nitrogen-containing hetero ring
    • C07J71/0042—Nitrogen only
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J11/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B60—VEHICLES IN GENERAL
    • B60R—VEHICLES, VEHICLE FITTINGS, OR VEHICLE PARTS, NOT OTHERWISE PROVIDED FOR
    • B60R16/00—Electric or fluid circuits specially adapted for vehicles and not otherwise provided for; Arrangement of elements of electric or fluid circuits specially adapted for vehicles and not otherwise provided for
    • B60R16/02—Electric or fluid circuits specially adapted for vehicles and not otherwise provided for; Arrangement of elements of electric or fluid circuits specially adapted for vehicles and not otherwise provided for electric constitutive elements
    • B60R16/03—Electric or fluid circuits specially adapted for vehicles and not otherwise provided for; Arrangement of elements of electric or fluid circuits specially adapted for vehicles and not otherwise provided for electric constitutive elements for supply of electrical power to vehicle subsystems or for

Definitions

  • vitamin D compounds such as cholecal- ciferol derivatives and metabolites thereof, promote both intestinal-calcium and phosphate transport and in conjunction with parathormone promote bone-calcium mobilization (bone resorbtion).
  • This differential effect has been widely sought for treatment of osteoporosis, especially that induced by an insufficient amount of calcium in relationship to the amount of phosphate.
  • the instant invention may be described as residing in the concept of a new and useful group of vitamin D 3 derivatives classifiable in the field of organic chemistry as 24-dehydrovitamin D 3 derivatives.
  • the novel 24-dehydrovitamin D 3 derviatives of the instant invention are members selected from the group consisting of 24-dehydrovitamin D 3 , 24- dehydro-1 ⁇ - hydroxy-vitamin D 31 24- ⁇ deydro-3 ⁇ -desoxy-1 ⁇ hydroxy-vitamin D 3 and 24-dehydro-3 ⁇ -desoxy-3 ⁇ -fluoro-vitamin D 3 .
  • novel compounds may be represented by the following structural formula: wherein R 1 is a member selected from the group consisting of hydrogen and hydroxy; R 2 is a member selected from the group consisting of hydrogen, hydroxy and fluoro; and wherein R 1 is not hydroxy when R 2 is fluoro.
  • the instant invention is based upon applicants' discovery that vitamin D 3 and derivatives may be metabolically blocked by the presence of a double bond at position C 24 -C 25 .
  • the presence of such double bond retards metabolic hydroxylation in vivo in the 25-position.
  • These novel 24- dehydrovitamin D 3 derivatives promote intestinal-calcium transport as opposed to bone-calcium mobilization.
  • compositions containing a therapeutically effective quantity of the novel 24-dehydrovitamin D 3 derivatives of this invention will be administered orally or parenterally to patients, including humans and warm-blooded animals, in need of vitamin D 3 therapy to promote intestinal-calcium transport and in the treatment of rickets, osteomalacia, and osteoporosis including steroid-induced osteoporosis, senile osteoporosis and post-menopausal osteoporosis.
  • 24-dehydrovitamin D 3 may be prepared readily by the photolysis of cholesta-5,7,24-trien-3 ⁇ -ol (J,P. Moreau, D. J. Aberhart and E. Caspi, J. Org. Chem., Vol. 39, No. 14, pp. 2018, 1974) in order to obtain 24-dehydroprevitamin D 3 .
  • the irradiation conveniently is carried out at low temperatures, about 0 to 5°C, in a suitable organic solvent, such as deoxygenated ether, using a 450 watt Hanovia medium pressure mercury vapor lamp. Photolysis under these conditions usually is carried out for as short as 2 minutes or up to about 1 hour but usually is in the range of 4 to 10 minutes while the reaction mixture is under a blanket of nitrogen.
  • the photolysate usually will contain a mixture of vitamin and previtamin together with some starting material and/or other isomeric forms.
  • the desired previtamin usually is the predominating product and can be separated and purified by low temperature preparative thin layer chromatography on silica gel plates (1000 or 2000 ⁇ ) at about 5°C developed with a suitable organic solvent or solvent mixture such as, for example, 10 to 15% acetone in hexane. Desirably the purification is carried out in the dark.
  • the purified 24-dehydroprevitamin D 3 then is dissolved in a suitable organic solvent such as deoxygenated ethanol and heated at relux for 1 to 2 hours.
  • a suitable organic solvent such as deoxygenated ethanol and heated at relux for 1 to 2 hours.
  • the desired 24-dehydrovitamin D 3 is separated and purified by low temperature preparative thin layer chromatography as described above.
  • the starting cholesta-5,7,24- trien-38-ol may be prepared from the known cholesta 5,7,-dien-3 ⁇ ,25-diol-3-acetate by first treating this diene in a suitable organic solvent such as methylene chloride, chloroform, carbon tetrachloride, ethyl acetate and the like with 4-phenyl-1,2,4-triazoline-3,5-dione in order to prepare the 4-phenyl-1,2,4-triazoline-3,5-dione adduct and to protect the cholesta 5,7-diene system during subsequent dehydration.
  • a suitable organic solvent such as methylene chloride, chloroform, carbon tetrachloride, ethyl acetate and the like
  • 4-phenyl-1,2,4-triazoline-3,5-dione in order to prepare the 4-phenyl-1,2,4-triazoline-3,5-dione adduct and to protect the
  • a suitable organic solvent such as benzene, hexane, xylene and the like
  • 24-dehydro-1 ⁇ -hydroxyvitamin D 3 may be prepared from the known cholesta-5,7-dien-1a,3 ⁇ ,25- triol-1,3-diacetate by treating this compound with a dehydrating agent such as methyl (carboxysul- famoyl) triethylammonium hydroxide inner salt in dry benzene or other suitable organic solvent such as toluene or xylene in order to obtain cholesta-5,7,24-trien-1a,3 ⁇ -diol-1,3-diacetate together with the corresponding 5,7,25-triene.
  • the reaction conveniently is carried out at the reflux temperature of the solvent under an inert atmosphere and usually requires about 20 to 60 minutes for completion.
  • 24-dehydro-3 ⁇ -desoxy-3 ⁇ -fluoro-vitamin D 3 may be prepared from the known 25-hydroxycholesterol dibenzoate by first selectively hydrolyzing this compound at the 3-position with an alkali metal hydroxide such as 2.5 N aqueous sodium hydroxide to give 25-benzoyloxycholesterol.
  • the reaction conveniently is carried out in a suitable solvent such as tetrahydrofuran, ethanol or mixtures thereof under an inert atmosphere. Completion of the reaction requires 36 to 60 hours at room temperature. Removal of the solvent gives the crude product which is purified by conventional recrystallization.
  • the 25-benzoyloxycholesterol then is treated with a fluorinating agent such as diethylaminosulfur trifluoride in a suitable organic solvent such as methylene chloride, chloroform, ethyl acetate and the like at low temperatures ranging from about -80 to -60°C under an inert atmosphere.
  • a fluorinating agent such as diethylaminosulfur trifluoride
  • a suitable organic solvent such as methylene chloride, chloroform, ethyl acetate and the like
  • the 25-benzoyloxy-38-fluorocholest-5-ene then is treated with a brominating agent such as dibromodimethyl- hydantoin in boiling hexane under nitrogen and refluxed for about 30 minutes to give 25-benzoyloxy-3A-fluoro-7-bromocholest-5-ene which is dissolved in a suitable organic solvent such as xylene and added to a refluxing solution of trimethylphosphite in the same solvent also under nitrogen. The mixture is refluxed for about an hour and concentrated to give a crude mixture of 25-benzoyloxy-3 ⁇ -fluorocholest-5,7-diene along with the corresponding 4,6-diene.
  • a brominating agent such as dibromodimethyl- hydantoin in boiling hexane under nitrogen
  • a suitable organic solvent such as xylene
  • trimethylphosphite trimethylphosphite
  • This diene mixture then may be treated with 4-phenyl-1,2,4-triazoline-3,5-dione as previously described in order to obtain cyclo adducts. Chromatography on silica gel eluting with methylene chloride gives the desired 4-phenyl-l,2,4-triazoline-3,5-dione adduct of 25-benzoyloxy-3b-fluoro-cholesta-5,7-diene.
  • the above eholesta-5,7-diene cyclo adduct then is converted to 3 ⁇ -fluorocholesta-5,7-dien-25-ol by treatment with lithium aluminum hydride in a refluxing organic solvent such as tetrahydrofuran.
  • a refluxing organic solvent such as tetrahydrofuran.
  • the mixture is refluxed for 30 to 90 minutes desirably in the dark and under an inert atmosphere.
  • the 3 ⁇ -fluorocholesta-5,7-dien-25-ol so produced then is dehydrated with methyl(carboxysulfa- moyl)triethylammonium hydroxide inner salt as previously described to obtain 3 ⁇ -fluorocholesta-5,7,24-triene which is subjected to irradiation and isomerization as described above to obtain, respectively,24-dehydro-3 ⁇ -desoxy-3 ⁇ -fluoro-vitamin D 3 and 24-dehydro-3 ⁇ -desoxy-3 ⁇ -fluoro vitamin D 3 .
  • 24-dehydro-3 ⁇ -desocy-1 ⁇ -hydroxyvitamin D 3 may be prepared from 1 ⁇ ,25-dihydroxycholesta-5,7-diene (W. H. Okamura, M. N. Mitra; D. A. Procsal and A. W. Norman, Biochem. and Biophys. Res. Comm., Vol. 65, No. 1, pp 24, 1975) by first selectively acetylating this compound at the 1-position with an acetylating agent such as acetic anhydride. The reaction conveniently is run in an organic solvent such as pyridine initially at a temperature between 0 0 and 5°C. After addition of the acetic .
  • an organic solvent such as pyridine
  • the acetoxy group at the 1-position then may be removed by conventional basic hydrolysis employing an alkali metal hydroxide such as 2.5 N aqueous sodium hydroxide to obtain 1a-hydroxycholesta-5,7,24- triene which then may be irradiated and isomerized by techniques described above to obtain, respectively, 24-dehydro-3 ⁇ -desoxy-1a-hydroxy-previtamin D 3 and 24-dehydro-3 ⁇ -desoxy-1a-hydroxyvitamin D 3 .
  • an alkali metal hydroxide such as 2.5 N aqueous sodium hydroxide
  • compositions for promoting intestinal-calcium transport and for treating osteoporosis comprising a therapeutically effective quantity of the 24- dehydrovitamin D 3 derivatives described above as the essential active ingredient together with a non-toxic pharmaceutically acceptable carrier.
  • Such compositions also may be used in the treatment of secondary hyperparathyroidis, especially that induced by an insufficient amount of calcium in relationship to the amount of phosphate.
  • the non-toxic pharmaceutical carrier may be, for example, either a solid or liquid.
  • solid carriers are lactose, corn starch, gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba, sucrose, agar, pectin and acacia.
  • liquid carriers are peanut oil, olive oil, sesame oil and water.
  • the carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate, alone, or with a wax.
  • the treatment of osteoporosis and secondary hyperparathyroidism in accordance with the method of the present invention is accomplished by orally or parenterally administering to patients a compound of formula I supra, or mixtures thereof in a non-toxic pharmaceutically acceptable carrier.
  • compositions may take the form of tablets, capsules, powders, troches or lozenges, prepared by standard pharmaceutical techniques.
  • a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, a syrup, a liquid solution, a liquid emulsion or a liquid suspension.
  • the active compounds of formula I, supra, are administered in a therapeutically effective amount sufficient to treat osteoporosis and secondary hyperparathyrbidis,.
  • the metabolically blocked 24-dehydrovitamin D 3 derivatives will reduce the bone mobilization in those cases wherein clinical symptoms have not been observed, e.g., administered prophylactically to persons subject to steroid induced osteoporosis, and in addition retard bone mobilization in those cases wherein clinical symptoms have been observed, e.g., senile osteoporosis, post-menopausal osteoporosis and secondary hyperparathyroidism.
  • the active compounds of formula I, supra will be administered alone or in a pharmaceutical composition in an amount of from about 1.0 to 3000 International Units (IU) per day, preferably from about 10 to 500 IU/day.
  • Standard preparations of vitamin D 3 have an activity of about 40 IU/ ⁇ g.
  • the daily dosage may be given either in single or multiple dosages.
  • the method of treatment of this invention comprises administering to a patient (warm-blooded animal or human) the compound of formula I, supra, as previously described admixed with a non-toxic pharmaceutical carrier such as exemplified above.
  • a patient warm-blooded animal or human
  • a non-toxic pharmaceutical carrier such as exemplified above.
  • Step A 4-phenyl-1,2,4-triazoline-3,5-dione Adduct of Cholesta-5,7-dien-3 ⁇ ,25-diol-3-acetate
  • Step B 4-phenyl-1,2,4-triazoline-3,5-dione Adduct of Cholesta-5,7,24-trien-3,5-ol-3-acetate
  • the combined tetrahydrofuran solution is concentrated in vacuo and extracted with chloroform (200 ml).
  • the chloroform solution is washed with water, brine and dried.
  • the crude product is purified by low temperature preparative thin layer chromatography on silica gel plates (2000 ⁇ ) at 5°C in the dark and developed with 6.5% acetone in chloroform.
  • the main zone is extracted with 5% methanol in chloroform in the cold. Removal of the solvent followed by recrystallization from methanol yields the title product (503 mg, m.p. 104-107°C).
  • the photo irradiated gross mixture is purified by low temperature preparative thin layer chromatography on silica gel plates (2000 ⁇ ) at 5°C developed with 15-16% acetone in hexane. The main zone is concentrated to a residue to obtain the title product (90 mg).
  • Step A Cholesta-5,7,24-trien-1 ⁇ ,3 ⁇ -diol-1, 3-diacetate
  • the purified 24-dehydro-la-hydroxyprevitamin D 3 diacetate of Step B is dissolved in deoxygenated absolute alcohol and heated under reflux for 2 hours.
  • the resulting solution containing a mixture of vitamin and previtamin is added to an equal volume of tetrahydrofuran and ethanol and one- fifth volume of 2.5 N sodium hydroxide solution under nitrogen at room temperature and allowed to stand overnight.
  • Low temperature preparative thin layer chromatography of the hydrolysis mixture in the dark on silica gel plates (1000 ⁇ ) at 5°C developed with 15% acetone in chloroform gives the title product.
  • Step C 4-phenyl-l,2,4-triazoline-3,5-dione Adduct of 25-Benzoyloxy-3 ⁇ -fluorocholesta-5,7- diene
  • Step E 3B-fluorocholesta-5,7,24-triene
  • Step F 24-dehydro-3 ⁇ -desoxy-3 ⁇ -fluoroprevitamin D 3
  • 35-fluorocholesta-5,7,24-triene (100 mg) in deoxygenated ether (500 ml) is irradiated in a quartz photocell at 0 to 5°C for 6 minutes using a 450 watt Hanovia medium pressure mercury vapor lamp while a stream of nitrogen is bubbled through the solution.
  • the photolysate is purified by low temperature preparative thin layer chromatography in the dark on silica gel plates (2000 ⁇ ) developed with 10% acetone in hexane at 5°C to give the title product.
  • Step G 24-dehydro-3 ⁇ -desoxy-3 ⁇ -fluorovitamin D 3
  • 24-dehydro-3 ⁇ -desoxy-3 ⁇ -fluoroprevitamin D 3 (35 mg) is dissolved in deoxygenated absolute alcohol and heated to reflux under nitrogen for 2 hours.
  • the resulting mixture of vitamin and previtamin is separated and purified by low temperature preparative thin layer chromatography in the dark on silica gel plates (2000 ⁇ ) developed with 10% acetone in hexane at 5°C to give the title product.
  • Step A 1 ⁇ -acetoxy-25-hydroxycholesta-5,7-diene
  • Step B la-acetoxycholesta-5,7,24-triene
  • 1 ⁇ -hydroxycholesta-5,7,24-triene 50 mg
  • deoxygenated ether 500 ml
  • the photolysate is purified by low temperature preparative thin layer chromatography in the dark on silica gel plates (2000 ⁇ ) at 5°C developed with 15% acetone in hexane to give the title product.
  • 24-dehydro-3 ⁇ -desoxy-1 ⁇ -hydroxyprevitamin D 3 (40 mg) is dissolved in deoxygenated absolute ethanol and heated to reflux under nitrogen for 2 hours.
  • the resulting mixture of vitamin and previtamin is purified by low temperature preparative thin layer chromatography in the dark on silica gel plates (2000 ⁇ ) at 5% developed with 15% acetone in hexane to give the title product.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Diabetes (AREA)
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  • Obesity (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP78100144A 1977-06-13 1978-06-13 24-Dehydrovitamin D3 Derivate und Verfahren zu ihrer Herstellung und diese enthaltende Präparate Withdrawn EP0000073A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US80567777A 1977-06-13 1977-06-13
US805677 1977-06-13

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EP0000073A1 true EP0000073A1 (de) 1978-12-20

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EP (1) EP0000073A1 (de)
JP (1) JPS545960A (de)
DK (1) DK261278A (de)
IT (1) IT1106130B (de)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0455503A1 (de) * 1990-05-04 1991-11-06 Colgate-Palmolive Company Zusammensetzung zur Behandlung von Osteoporose und Hormongleichgewichtsstörung
WO1993021205A1 (en) * 1992-04-15 1993-10-28 Sri International Isolation of steroids containing a 5,7-diene functionality from a sterol mixture
CN106831921A (zh) * 2016-12-15 2017-06-13 浙江工业大学 一种25‑羟基‑7‑去氢胆固醇的制备方法

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS58126861A (ja) * 1981-11-02 1983-07-28 リサ−チ・インステイチユ−ト・フオア・メデイスン・アンド・ケミストリ−・インコ−ポレ−テツド 新規化合物およびその製法
JPH0613342B2 (ja) * 1986-01-30 1994-02-23 雅也 松田 ラベル類の貼着機
JP2518615B2 (ja) * 1986-05-27 1996-07-24 株式会社フジシール フイルム送給装置
CN117126089A (zh) * 2023-08-30 2023-11-28 正大制药（青岛）有限公司 一种氟骨化醇25-羟基消除化合物的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2162113A1 (de) * 1971-12-02 1973-07-13 Wisconsin Alumni Res Found
US3906014A (en) * 1974-06-17 1975-09-16 Wisconsin Alumni Res Found 3-Deoxy-1{60 -hydroxycholecalciferol

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2162113A1 (de) * 1971-12-02 1973-07-13 Wisconsin Alumni Res Found
US3906014A (en) * 1974-06-17 1975-09-16 Wisconsin Alumni Res Found 3-Deoxy-1{60 -hydroxycholecalciferol

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 82 (1975) 80397r & Ukr. Biokhim. Zh. 1974 46 (5) 627-30 *
TETRAHEDRON LETTERS, vol. 13, 1977, pages 1107-1108 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0455503A1 (de) * 1990-05-04 1991-11-06 Colgate-Palmolive Company Zusammensetzung zur Behandlung von Osteoporose und Hormongleichgewichtsstörung
GR910100192A (en) * 1990-05-04 1992-07-30 Colgate Palmolive Co Method for preparing a composition for the osteoporosis and hormone imbalance treatment
WO1993021205A1 (en) * 1992-04-15 1993-10-28 Sri International Isolation of steroids containing a 5,7-diene functionality from a sterol mixture
US5391777A (en) * 1992-04-15 1995-02-21 Sri International Isolation of steroids containing a 5,7-diene functionality from a sterol mixture
CN106831921A (zh) * 2016-12-15 2017-06-13 浙江工业大学 一种25‑羟基‑7‑去氢胆固醇的制备方法

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IT7849828A0 (it) 1978-06-12
JPS545960A (en) 1979-01-17
DK261278A (da) 1979-12-15
IT1106130B (it) 1985-11-11

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