WO2008128782A2 - Procédé photochimique d'obtention de prévitamine d - Google Patents

Procédé photochimique d'obtention de prévitamine d Download PDF

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Publication number
WO2008128782A2
WO2008128782A2 PCT/EP2008/003320 EP2008003320W WO2008128782A2 WO 2008128782 A2 WO2008128782 A2 WO 2008128782A2 EP 2008003320 W EP2008003320 W EP 2008003320W WO 2008128782 A2 WO2008128782 A2 WO 2008128782A2
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Prior art keywords
previtamin
derivative
dehydrosterol
process according
conversion
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PCT/EP2008/003320
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English (en)
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WO2008128782A3 (fr
Inventor
Rafael Reintjens
Andreas Puhl
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Dsm Ip Assets B.V.
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Publication of WO2008128782A2 publication Critical patent/WO2008128782A2/fr
Publication of WO2008128782A3 publication Critical patent/WO2008128782A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation

Definitions

  • the present invention relates to a photochemical process for the preparation of a previtamin D or a derivative thereof from a 7-dehydrosterol at low conversion of 7- dehydrosterol.
  • previtamin D 3 may be obtained from 7-dehydrocholesterol (7-DHC, provitamin D 3 ) by irradiation with UV light. In this photochemical step the 9,10-bond of 7-DHC is cleaved to give the (Z)-triene previtamin D 3 . This previtamin may be converted by thermal rearrangement into vitamin D 3 which is thermally more stable. Unfortunately, previtamin D 3 can also absorb photons and convert to unwanted byproducts such as lumisterol and tachysterol (see Scheme 1).
  • EP-A-O 118 903 describes the irradiation of 7-DHC at 50 % conversion by using a laser which emits monochromatic UV light having a wavelength at or near the optimum value for the photochemical cleavage of the 9,10-bond of the starting material.
  • the previtamin D 3 selectivity is reported to be at least 80 %.
  • Laser photon sources are not suitable for photochemical synthesis of previtamin D 3 on an industrial scale because of their high technical complexity and the fact that their radiation geometry has little suitability for preparative photochemistry and the associated radiation density is insufficient over a large area.
  • EP-A-O 967 202 discloses a photochemical process for the production of previtamin D 3 at 50 % conversion wherein the UV radiation source is an excimer or exciplex emitter which emits quasi-monochromatically in the optimum UV range according to the "corona discharge" mechanism.
  • the previtamin D 3 selectivity is reported to be about 93 %.
  • US-A-4,388,242 and US-A-4,686,023 describe methods of production of previtamin D 3 (or D 2 ) involving a two-step irradiation wherein in a first irradiating step 7-DHC is converted to a minor proportion of previtamin D 3 and a major proportion of tachysterol which is then converted to previtamin D 3 in a second irradiating step.
  • the first irradiating step is conducted at high conversion of 7-DHC, for example more than 90 % conversion can be calculated from the examples of US-A-4,686,023.
  • double irradiation requires additional reaction equipment and increases production costs.
  • the object of the present invention is to provide a new photolytic process for the preparation of a previtamin D, especially previtamin D 3 , from a 7-dehydrosterol, which process results in low amounts of unwanted byproducts, avoids the use of elaborate multistep irradiations and does not require the use of expensive UV light sources.
  • the new photolytic process should be suitable for the industrial production of previtamin D 3 and other previtamins D on large scale.
  • R 2 is H; R 3 is H; and R 4 is H, CH 3 or C 2 H 5 ,
  • the present invention is further directed to a process for the preparation of a vitamin D according to formula (III)
  • Fig. 1 is a graph depicting the selectivity towards previtamin D 3 versus conversion of 7- DHC for an irradiation at a wavelength of 254 ran,
  • Fig. 2 is a graph depicting the selectivity towards previtamin D 3 versus conversion of 7- DHC for an irradiation at a wavelength of 282 nm.
  • Fig. 3 is a flow diagram of the irradiation process described in Examples 1 and 2.
  • Fig. 4 is a flow diagram of the irradiation process described in Examples 3, 4, 5 and 6.
  • Fig. 5. is flow diagram of the separation process described in Example 6.
  • a previtamin D or a derivative thereof is prepared with high selectivity at low conversion, i.e. less than 12 % maximum conversion of the starting material 7-dehydrosterol.
  • the 7-dehydrosterol is irradiated until a maximum conversion of 10 % or less than 10 % is reached.
  • the 7- dehydrosterol is irradiated until a maximum conversion of 7 % or less than 7 % is reached and in other embodiments, the 7-dehydrosterol is irradiated until a maximum conversion of about 5 % is reached.
  • Irradiating until a certain maximum conversion is reached means that the photochemical process is conducted in a way that higher conversions are avoided. For example, irradiating until a conversion of less than 12 % is reached means that conversions of 12 % or higher are avoided. In case of a batch process this means termination of the photochemical process at a conversion of less than 12 %; in case of a continuous process this means adjusting the average residence time short enough to maintain the process at a conversion below 12 %. Corresponding statements are applicable for the other maximum conversions mentioned above.
  • the selectivity for the previtamin D or the derivative thereof is at least 80 %, in some embodiments at least 85 %, in other embodiments at least 90 % and in still other embodiments at least 95 %.
  • the theoretical selectivity for a previtamin D or the derivative thereof that can be achieved depends on the conversion and on the wavelength of the UV light used for irradiation.
  • the present inventors performed calculations based on a simplified kinetic model for the photochemical conversion of 7-DHC to previtamin D 3 and the unwanted byproducts lumisterol and tachysterol (see Scheme 1). Taking into account the wavelength dependency of the quantum yield and the molar absorption coefficient of the components involved, the dependency of the selectivity from the conversion can be depicted as it is shown in Fig. 1 and 2 for an irradiation wavelength of 254 nm and 282 run, respectively. It is evident from the figures that the selectivity towards previtamin D 3 decreases with increasing conversion for both wavelengths.
  • the descending gradient is less steep in case of irradiation at the optimum wavelength of about 282 nm, meaning that the irradiation process can be conducted at relatively higher conversion still resulting in high selectivity for the previtamin D or the derivative thereof.
  • a similar graph is obtained in case of irradiation at a wavelength of about 296 nm which corresponds to the second dominant peak in the absorption spectrum of 7-DHC. If the irradiation is performed at a less optimum wavelength , e.g. 254 nm, it must be interrupted at relatively lower conversion in order to achieve a reasonably high selectivity.
  • a conversion of 10 % results in a theoretical selectivity of more than 95 % at 282 nm or 296 nm and in a selectivity of only about 85 % at 254 nm.
  • the actual selectivity achievable in a real reaction system is always lower than the theoretical values.
  • the 7-dehydrosterol is preferably irradiated until a conversion of at least 2 % is reached.
  • the present photochemical process is not restricted to any specific type of UV radiation source.
  • useful UV radiation sources include quasi-monochromatic UV radiation sources emitting light having a wavelength between 270 and 300 ran, e.g. XeBr or Br 2 excimer lamps, certain lasers, such as excimer lasers or exciplex lasers, and UV LEDs, as well as polychromatic UV radiation sources, such as the standard mercury medium pressure lamp emitting a line spectrum with an intensive line at 254 nm which is not the optimum wavelength.
  • the present process is not restricted to the preparation of previtamin D 3 but can be used to prepare various compounds of the vitamin D group as defined above, including derivatives, because all their provitamins (the 7-dehydrosterols) have the same 4-ring steroid skeleton with two double bonds in the 5- and 7-position (steroidal 5,7-dienes), the 5,7 diene structure being responsible for the photochemical behavior of these compounds.
  • previtamin D 2 /vitamin D 2 and previtamin D 3 /vitamin D 3 are preferred.
  • the process according to the present invention comprises in addition to the irradiation step (a) the additional step of (b) separating at least part of the unconverted 7-dehydrosterol or the derivative thereof from the reaction mixture. More preferably, the process further comprises the subsequent step of (c) recycling the separated part of the unconverted 7-dehydrosterol to the irradiation step (a). The recycling of the unconverted 7-dehydrosterol increases the economic viability of the process.
  • the unconverted 7-dehydrosterol is recycled at least once, preferably at least times times, more preferably at least 15 times and most preferably at least 20 times, hi a preferred embodiment, the process is conducted continuously comprising continuous recycling of the unconverted 7-dehydrosterol.
  • At least 90 %, preferably at least 95 %, more preferably at least 98 %, and most preferably at least 99 % of the unconverted 7-dehydrosterol are separated from the reaction mixture and recycled to the irradiation step.
  • the break even point where the recycling costs balance the selectivity gain is reached at about 5 % conversion In one embodiment of the present invention using a mercury medium-pressure lamp for irradiation and showing a strong dependence of the selectivity on the conversion, the break even point where the recycling costs balance the selectivity gain is reached at about 5 % conversion.
  • the 7-dehydrosterol to be irradiated is dissolved in a suitable solvent.
  • a suitable solvent any solvent, preferably organic solvent, that does not absorb or has low absorbency for UV radiation above 240 nm and sufficiently dissolves the 7-dehydrosterol or the derivative of interest can be used.
  • solvents preferably organic solvent, that does not absorb or has low absorbency for UV radiation above 240 nm and sufficiently dissolves the 7-dehydrosterol or the derivative of interest
  • examples include lower alcohols such as methanol, ethanol and 1- propanol; simple ethers, such as diethylether; cyclic ethers, such as tetrahydrofuran and 1 ,4-dioxane; unsymmetrical ethers, such as tert-butyl methyl ether; alkanes, such as n- hexane, and mixtures thereof.
  • the preferred solvent used to convert the 7-dehydrosterol, especially 7-DHC, to the previtamin D is a mixture of methanol and n-hexane, preferably in a volume ratio of 2:1.
  • the concentration of the 7-dehydrosterol, e.g. 7-DHC, in the solvent is within the range of from 1 to 15 % by weight, preferably from 5 to 10 % by weight.
  • the 7-dehydrosterol is dissolved in a mixture of methanol and n-hexane at a concentration of 7 to 10 % by weight.
  • the irradiation may be performed in the presence of a free radical scavenger, e.g. tert- butyl hydroxy anisole (BHA), to minimize degradation of previtamin D.
  • a free radical scavenger e.g. tert- butyl hydroxy anisole (BHA)
  • BHA tert- butyl hydroxy anisole
  • the irradiation temperature does not effect the photochemical reaction. Generally, the temperature is selected to provide solubility of the 7-dehydrosterol in the solvent employed. Depending on the type of solvent and specific 7-dehydrosterol employed, the irradiation is typically performed at a temperature within the range of from -20 to 60°C, preferably form 0 to 50°C, more preferably from 10 to 45°C, and most preferably from 25 to 45°C.
  • the typical temperature range for the irradiation is from 0 to 60°C, preferably form 10 to 50°C, more preferably from 20 to 45°C, even more preferably from 30 to 45°C, and most preferably from 35 to 45°C.
  • the present photochemical process may be conducted in any reactor suitable for photoreactions that provides enough irradiation surface (meaning low enough UV power density (W/m 2 )).
  • the reactor design is not critical for the present invention and it is within the ordinary skill of the scientist to select an appropriate reactor design.
  • the 7-dehydrosterol may be irradiated in a falling-film reactor, especially suitable for production of previtamin D on an industrial scale.
  • the irradiation may be repeated once or several times until the desired conversion is reached. The repetition of the irradiation may be accomplished batchwise or continuously by circulating the solution of the 7-dehydrosterol through the falling-film reactor.
  • the separation of the 7-dehydrosterol in step (b) involves at least one, preferably at least two, more preferably two crystallization steps.
  • the crystallization step at least part of the unreacted 7-dehydrosterol is precipitated from the solvent, typically by cooling, and thereafter the precipitated 7- dehydrosterol is separated from the solvent by solid/liquid separation, e.g. by centrifugation or filtration, preferably centrifugation, and finally the 7-dehydrosterol is recycled back to the radiation step.
  • a distilling step is performed between the first and second crystallization steps.
  • the distillation step at least part of the solvent is removed to promote the precipitation of the 7-dehydrosterol. Due to the temperature sensitivity of the previtamin D (premature isomerization to vitamin D should be avoided) as well as of the unwanted, but defined byproducts that should not be converted to unknown products, the distillation step is preferably conducted at mild conditions, i.e. reduced pressure, thus avoiding high temperature.
  • n-hexane preferably in a volume ratio of 2:1
  • the present inventors have discovered that a mixture of methanol and n-hexane, preferably in a volume ratio of 2:1, is the preferred solvent for the separation procedure involving two crystallization steps and one intermediate distilling step.
  • the distillation step most of the n-hexane, preferably the total n-hexane, is removed from the methanol.
  • the 7-dehydrosterol may start to crystallize from the solution and if the slurry concentration becomes to high, it may be necessary to add some additional methanol.
  • the "solvent switch" that is performed during distillation of the methanol/n- hexane solution is also applicable to other solvent systems.
  • the 7-dehydrosterol that is harvested from each of the crystallization steps is recycled back to the radiation step or a preceding dissolving step wherein fresh and recycled 7- dehydrosterol are dissolved in a suitable solvent, preferably a mixture of methanol and n- hexane, prior to the irradiation step.
  • a suitable solvent preferably a mixture of methanol and n- hexane
  • the solvent that is distilled off in the distillation step may also be recycled to the irradiation step or the preceding dissolving step, respectively.
  • the mother liquor that remains after the last crystallization step comprises the reaction products, i.e.
  • the previtamin D or the derivative thereof, unwanted byproducts and optionally unreacted 7-dehydrosterol in minor amounts that has not been separated completely due to a certain solubility of the 7-dehydrosterol in the solvent may further reduce the amount of 7-dehydrosterol in the solvent by decreasing the temperature of the last crystallization step and/or conducting a third and optionally further crystallization steps.
  • economical considerations may decide that the small amount of additional 7-dehydrosterol that is recycled by these measures do not justify the additional costs for cooling and/or further crystallization steps.
  • a "loss" of 7- dehydrosterol of about 1 to 2 % (based on the produced previtamin) in the final mother liquor due to its solubility represent the economic optimum.
  • the process further comprises recovering the previtamin D.
  • Suitable methods to recover the previtamin D are known to the person skilled in the art and include commonly used separation procedures, such as for example chemical conversion of byproducts, e.g. tachysterol; and industrial chromatography. It is a matter of fact that the purification of the previtamin D is much easier if it is obtained with high selectivity as it is possible by employing the present process.
  • the present invention is also directed to the preparation of a vitamin D or a derivative thereof by thermal rearrangement of the previtamin D or the corresponding derivative thereof.
  • the thermal conversion to the vitamin D is a sigmatropic 1,7-hydrogen shift from C- 19 to C-9 and is done at a suitable point in the process after the photochemical reaction; for example, the thermal conversion may be performed before or after the separation of the 7-dehydrosterol.
  • the thermal rearrangement of the previtamin D during photolysis should be avoided because the vitamin D itself (or its derivatives) can also undergo photoconversion which results in further unwanted byproducts.
  • the process in accordance with the present invention also includes the preparation of vitamin D derivatives and previtamin D derivatives by irradiating the corresponding derivatives of the 7-dehydrosterols.
  • Derivatives of 7-dehydrosterol include all analogous compounds having the 4-ring steroid nucleus as shown in formula (II) wherein the 9,10- bond can be cleaved photochemically to give the corresponding (Z)-triene.
  • Such analogous compounds may have any additional substituents thereon, provided the substituents do not interfere in the photochemical conversion. All statements made within this application equally apply to the derivatives of vitamins D, previtamins D and 7- dehydrosterols.
  • the derivates include but are not limited to hydroxylated and ester derivatives. More specifically the derivative of a previtamin D is an ester derivative or a derivative according to formula (I)
  • R is ( ⁇ ), R >2 is H, a hydroxy or acyloxy group; R 3 is H, a hydroxy or acyloxy group; and R 4 is H, CH 3 , C 2 H 5 , a hydroxy or acyloxy group; provided that least one of R > 2 , n R3 and R is a hydroxy or acyloxy (ester) group.
  • esters means derivatives wherein the 3-OH group is esterified with an organic acid and includes (a) previtamin D esters according to formula (IV)
  • R is 1 r 7 r* 3 (i) or 1 r 7 r* 3 (ii),
  • R 2 is H;
  • R 3 is H;
  • R 4 is H, CH 3 or C 2 H 5 , and
  • R 5 is an acyl group, preferably having 1 to 10 carbon atoms, e.g. acetyl and benzoyl; as well as (b) esters of previtamin D derivatives, the esters being represented by formula
  • R 2 is H, a hydroxy or acyloxy group
  • R 3 is H, a hydroxy or acyloxy group
  • R 4 is H, CH 3 , C 2 H 5 , a hydroxy or acyloxy group
  • R 5 is an acyl group, preferably having 1 to 10 carbon atoms, e.g. acetyl and benzoyl; provided that least one of R 2 , R 3 and R 4 is a hydroxy or acyloxy (ester) group.
  • Examples of derivatives of previtamin D/vitamin D include l ⁇ -hydroxy previtamin D 3 /l ⁇ -hydroxy vitamin D 3 (l ⁇ -hydroxycholecalciferol or alfacalcidiol); l ⁇ -hydroxy previtamin D 2 /l ⁇ -hydroxy vitamin D 2 (1 ⁇ -hydroxyergocalciferol); 25-hydroxy previtamin D 3 /25-hydroxy vitamin D 3 (25-hydroxycholecalciferol or calcidiol or calcifediol or Hy- D®); 25-hydroxy previtamin D 2 /25-hydroxy vitamin D 2 (25-hydroxyergocalciferol); l ⁇ ,25-dihydroxy previtamin D 3 /l ⁇ ,25-dihydroxy vitamin D 3 (l ⁇ ,25- dihydroxycholecalciferol, calcitriol); l ⁇ ,25-dihydroxy previtamin D 2 /l ⁇ ,25-dihydroxy vitamin D 2 (l ⁇ ,25-dihydroxyergocalciferol); 1 ⁇ ,24-d
  • the previtamin is prepared by irradiating its corresponding provitamin.
  • previtamin D derivative is prepared by irradiating the corresponding derivative of the 7-dehydrosterol:
  • 25-hydroxy previtamin D 3 is prepared by irradiating the 25-hydroxy derivative of 7-DHC (25-hydroxy provitamin D 3 ).
  • an ester of previtamin D 3 is prepared by irradiating the corresponding ester derivative of 7-DHC.
  • reaction set-up as shown in Fig. 3 employing a falling-film reactor as the photo irradiation reactor (B) was used.
  • a solution of 7-DHC (provitamin D 3 ) was prepared by charging 1000 g of n-hexane (1), 500 g of methanol (1), 2 g of BHA (tert- butyl hydroxy anisole) and 80 g of 7-DHC (2) to the feed solution tank (A). At 35°C the content was stirred until all 7-DHC was dissolved.
  • the photo irradiation reactor (B) contained a 150 W mercury middle pressure lamp (C) which was electrically powered by the appropriate power supply (D).
  • the 7-DHC solution (3) was continuously fed to the photo reactor (B) and recycled back (4) to the feed solution tank (A) .
  • the experiment was started by switching on the mercury lamp (C). Irradiation was continued for 120 min. After switching off the mercury lamp (C) the solution was circulated for 15 minutes to homogenize. The final irradiated solution (5) was analyzed with high pressure liquid chromatography (HPLC). Conversion of 7-DHC: 5.5 %; selectivity for previtamin D 3 : 93.5 %.
  • This example also used the reaction set-up as shown in Fig. 3 but the irradiation was conducted in a falling-film reactor (B) that contained a 100 W XeBr excimer lamp (C).
  • B falling-film reactor
  • C 100 W XeBr excimer lamp
  • the example was carried out according to the procedure described in Example 1 except that 0.5 g of BHA were used instead of 2 g of BHA.
  • the reaction set-up as shown in Fig. 4 employing a falling-film reactor as the photo irradiation reactor (B) was used.
  • a solution of 7-DHC (provitamin D 3 ) was prepared by charging 4430 g of n-hexane (1), 2210 g of methanol (1), 0.5 g of BHA and 550 g of 7-DHC (2) to the feed solution tank (A). At 35°C the content was stirred until all 7-DHC was dissolved.
  • the photo irradiation reactor (B) contained a 1500 W mercury middle pressure lamp (C) which was electrically powered by the appropriate power supply (D). The mercury lamp (C) was switched on.
  • the experiment was started by starting the feed of 7-DHC solution (3) to the photo reactor (B).
  • the irradiated solution (5) was collected in the irradiated solution tank (E).
  • the irradiation ended when the feed solution tank (A) was empty.
  • Such a single irradiation did not result in the desired conversion, therefore the irradiation was repeated several times by transferring the irradiated solution (5) back to the feed solution tank (A) and irradiate it again in another pass.
  • the irradiated solution (5) was analyzed with HPLC Conversion of 7-DHC: 8.4 %; selectivity for previtamin D 3 : 86.7 %.
  • This example also used the reaction set-up as shown in Fig. 4 and it was carried out according to the procedure described in Example 3 except that the following amounts of starting materials were employed: 4420 g of n-hexane, 211O g of methanol, 1 g of BHA and 860 g of 7-DHC. They were stirred at 45°C until all 7-DHC was dissolved. Conversion of 7-DHC: 5.8 %; selectivity for previtamin D 3 : 89.0 %.
  • This example also used the reaction set-up as shown in Fig. 4 but the irradiation was conducted in a falling-film reactor (B) that contained a 3000 W XeBr excimer lamp (C).
  • a solution of 7-DHC was prepared by charging 6200 g of n-hexane (1), 3100 g of methanol (1), 1 g of BHA and 700 g of 7-DHC (2) to the feed solution tank (A). At 35°C the content was stirred until all 7-DHC was dissolved.
  • the XeBr excimer lamp (C) was switched on. The experiment was started by starting the feed of 7-DHC solution (3) to the photo reactor (B).
  • the irradiated solution (5) was collected in the irradiated solution tank (E).
  • the irradiation ended when the feed solution tank (A) was empty.
  • the irradiation was repeated several times by transferring the irradiated solution (5) back to the feed solution tank (A) and irradiate it again in another pass.
  • the irradiated solution (5) was analyzed with HPLC. Conversion of 7-DHC: 5.5 %; selectivity for previtamin D 3 : 96.2 %. After 6 passes it was analyzed again.
  • a solution of 7-DHC was prepared by charging 8800 g of n- hexane (1), 4400 g of methanol (1), 1 g of BHA and 1000 g of 7-DHC (2) to the feed solution tank (A). At 35°C the content was stirred until all 7-DHC was dissolved.
  • the falling-film reactor (B) contained a 3000 W XeBr excimer lamp (C) which was electrically powered by the appropriate power supply (D). The XeBr excimer lamp (C) was switched on. The experiment was started by starting the feed of 7-DHC solution (3) to the photo reactor.
  • the irradiation ended when the feed solution tank (A) was empty.
  • the desired conversion of 5.6 % was achieved in a single pass by adapting the flow of the feed solution.
  • a selectivity of 93.6% for previtamin D 3 was obtained after irradiation.
  • the first crystallizer (F) was charged with 3500 g of methanol and cooled to -20°C.
  • the irradiated solution (5) was continuously fed to the first crystallizer (F).
  • the 7-DHC crystals (8) were separated from the mother liquor (9), washed with cold methanol (7) and dried (yield of 1 st crop 563 g).
  • the mother liquor (9) including wash liquid was transferred to a batch distillation unit (H) and concentrated by evaporation until 4585 g remained in the bottom.
  • the bottom product (11) was transferred to a second crystallizer (J) and cooled down to -20°C. Again 7-DHC crystallized.
  • the 7-DHC crystals (14) were separated from the second mother liquor (15), washed with cold methanol (13) and dried (yield of 2 nd crop 366 g).
  • the obtained 7-DHC was recycled to the irradiation step, i.e. it was introduced into the feed solution tank (A) and then fed to the photo irradiation reactor (B) as described above.

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Abstract

L'invention concerne un procédé photochimique d'obtention de prévitamine D ou d'un dérivé de cette dernière à partir de 7-déhydrostérol ou d'un dérivé correspondant de cette substance. Ce procédé consiste à soumettre le 7-déhydrostérol ou son dérivé à une rayonnement ultraviolet jusqu'à atteindre un taux de transformation maximum du 7-déhydrostérol ou de son dérivé de moins de 12%.
PCT/EP2008/003320 2007-04-24 2008-04-24 Procédé photochimique d'obtention de prévitamine d WO2008128782A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8263580B2 (en) 1998-09-11 2012-09-11 Stiefel Research Australia Pty Ltd Vitamin formulation
US8298515B2 (en) 2005-06-01 2012-10-30 Stiefel Research Australia Pty Ltd. Vitamin formulation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110713449A (zh) * 2019-11-12 2020-01-21 广西师范大学 一种维生素d3的高效绿色生产工艺
CN110724081B (zh) * 2019-11-12 2023-08-15 广西师范大学 一种维生素d2的高效生产工艺

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0028484A1 (fr) * 1979-10-23 1981-05-13 Teijin Limited Procédé de préparation de composés ayant une activité de type vitamine D3 et des cholesta-5,7,diène précurseurs et produits obtenus
EP0967202A1 (fr) * 1998-06-23 1999-12-29 F. Hoffmann-La Roche Ag Photolyse du 7-dehydrocholesterol

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0028484A1 (fr) * 1979-10-23 1981-05-13 Teijin Limited Procédé de préparation de composés ayant une activité de type vitamine D3 et des cholesta-5,7,diène précurseurs et produits obtenus
EP0967202A1 (fr) * 1998-06-23 1999-12-29 F. Hoffmann-La Roche Ag Photolyse du 7-dehydrocholesterol

Non-Patent Citations (2)

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Title
I. P. TERENETSKAYA ET AL: "Analysis of the two-stage irradiation of provitamin D taking into account the irreversible photoreactions of previtamin" PHARMACEUTICAL CHEMISTRY JOURNAL., vol. 27, no. 11, 1993, pages 797-803, XP002499730 USCONSULTANTS BUREAU, NEW YORK, NY *
M. BRAUN ET AL: "Improved photosynthesis of previtamin D by wavelengths of 280-300 nm" JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY, A: CHEMISTRY., vol. 61, no. 1, 1991, pages 15-26, XP002499729 CHELSEVIER SEQUOIA, LAUSANNE. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8263580B2 (en) 1998-09-11 2012-09-11 Stiefel Research Australia Pty Ltd Vitamin formulation
US8298515B2 (en) 2005-06-01 2012-10-30 Stiefel Research Australia Pty Ltd. Vitamin formulation
US8629128B2 (en) 2005-06-01 2014-01-14 Stiefel West Coast, Llc Vitamin formulation

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