WO2008128783A2 - Photochemical process for the preparation of a previtamin d - Google Patents
Photochemical process for the preparation of a previtamin d Download PDFInfo
- Publication number
- WO2008128783A2 WO2008128783A2 PCT/EP2008/003321 EP2008003321W WO2008128783A2 WO 2008128783 A2 WO2008128783 A2 WO 2008128783A2 EP 2008003321 W EP2008003321 W EP 2008003321W WO 2008128783 A2 WO2008128783 A2 WO 2008128783A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- previtamin
- derivative
- hydroxy
- dhc
- dehydrosterol
- Prior art date
Links
Classifications
-
- 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 using UV LED(s) as UV radiation source.
- 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).
- previtamin D 3 Conventional photochemical synthesis of previtamin D 3 on an industrial scale reportedly has been effected by irradiation of 7-DHC using mercury medium-pressure lamps. Because the starting material (7-DHC), the primary product (previtamin D 3 ) as well as byproducts, absorb with different efficiency in the same wavelength range, polychromatic radiation of the kind supplied by these lamps favors the formation of photochemical byproducts which are inactive and in some cases toxic. Therefore, with the present state of the art, it is necessary to interrupt the irradiation after relatively low conversion of the 7- DHC to previtamin to D 3 . The unconverted 7-DHC is recycled while the primary product (previtamin D 3 ) must be purified in an expensive working up procedure.
- Filter effects are a further consequence of substrates and products which absorb in the same wavelength range. For example, when the absorption spectrum of previtamin D 3 overlaps completely with that of 7-DHC, the previtamin absorbs a continuously increasing proportion of the light as the conversion proceeds.
- Another reason for interrupting the conventional reaction after a relatively low conversion (10-20%) of 7-DHC to previtamin D 3 is the fact that the quantum yield (i.e., the efficiency) of the subsequent photochemical reaction of previtamin D 3 to, e.g. tachysterol, is greater than the quantum yield of the formation of the desired product (previtamin D 3 ).
- the efficiency of the reaction is decreased while the cost of production of the end product is increased.
- previtamin D 3 Another significant problem during conventional production of previtamin D 3 is the poor correlation between the emission spectrum of mercury medium-pressure lamps and the absorption spectrum of 7-DHC.
- mercury medium-pressure lamps only about 1% of the radiation radiating therefrom is in the desired range, i.e., between about 280 and about 300 ran.
- the radiation spectrum produced by a conventional mercury medium-pressure lamp is not optimized for the 280- 300 ran wavelength, a large amount of undesired byproducts are produced by irradiation outside this optimum wavelength region.
- EP-A-O 967 202 discloses a photochemical process for the production of previtamin D 3 wherein the UV radiation source is an excimer or exciplex emitter which emits quasi- monochromatically in the UV range according to the "corona discharge" mechanism.
- the UV radiation source is an excimer or exciplex emitter which emits quasi- monochromatically in the UV range according to the "corona discharge" mechanism.
- 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 avoids the drawbacks of the prior-art procedures.
- the new photolytic process should be suitable for the industrial production of previtamin D 3 , other previtamins D and derivatives thereof on large scale.
- R 2 is H; R 3 is H; and R 4 is H, CH 3 or C 2 H 5 ,
- UV light emitting diode(s) UV LED(s)
- the present invention is further directed to a process for the preparation of a vitamin D according to formula (III) - O -
- Fig. 3 shows the microreactor used in the examples.
- Fig. 4 shows the experimental setup used in the examples.
- previtamin D production from a 7-dehydrosterol is achieved by using as the radiation source UV light emitting diode(s) (UV LED(s)).
- UV LED(s) UV light emitting diode
- 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.
- a light emitting diode is a semiconductor device that emits incoherent narrow- spectrum, quasi-monochromatic light when electrically biased in the forward direction (electroluminescence).
- a LED is a unique type of semiconductor diode. Like a normal diode, it consists of a chip of semiconducting material impregnated, or doped, with impurities to create a p-n junction.
- UV LEDs have a direct band gap with energies corresponding to near-infrared, visible or near- ultraviolet light.
- UV LEDs are based on (AlGaIn)N built on a sapphire substrate.
- the actual material of the UV LED is not critical for the present invention.
- UV LEDs suitable for the present process are, for example, commercially available form SENSOR ELECTRONIC TECHNOLOGY, INC., South Carolina, U.S.A. under the trade mark UV TOP®.
- a single UV LED or a plurality of UV LEDs for example several individual UV LEDs that are clustered into a bigger system, may be used.
- the UV LEDs for use in the present process preferably emit UV light having a wavelength between 250 and 320 nm, more preferably between 270 and 300 nm. In one embodiment of the present invention the UV LEDs emit UV light having a wavelength of 280 nm ⁇ 10 nm. - o -
- 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 run 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 run 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 1-propanol or a mixture of methanol and n- hexane.
- concentration of the 7-dehydrosterol, e.g. 7-DHC, in the solvent is within the range of from 1 to 10 % by weight, preferably from 5 to 10 % by weight.
- the irradiation temperature does not effect the photochemical reaction.
- the temperature is selected to provide solubility of the 7-dehydrosterol in the solvent employed.
- the irradiation is typically performed at a temperature within the range of from -20 to 60 0 C, preferably form 0 to 50°C, more preferably from 10 to 45°C, and most preferably from 25 to 45°C.
- An irradiation temperature within the preferred ranges is typically used in combination with the preferred solvents mentioned above.
- 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 present photochemical process may be conducted in any reactor suitable for photoreactions.
- the reactor design is not critical for the present invention.
- the 7-dehydrosterol may be irradiated in a falling- film reactor, especially suitable for production of previtamin D on an industrial scale.
- the use of a microreactor in combination with a small UV LED enables production of small quantities of previtamin D
- previtamin D 3 preparation 7-DHC, previtamin D 3 and the unwanted byproducts lumisterol and tachysterol form a photochemical equilibrium. - -
- Fig. 1 shows the effect of a wavelength of 254 ran on the reaction course and is representative for radiating with a mercury medium-pressure lamp emitting a line spectrum with an intensive line at 254 nm (effect of the other emission lines omitted).
- Fig. 2 shows the effect of a wavelength of 282 nm on the reaction course and is representative for radiating with UV LED(s).
- previtamin D 3 not more than 5 %, in order to obtain a very high selectivity for previtamin D 3 , e.g. at least 96 %.
- slightly higher conversions will result in slightly lower, though still high selectivities for previtamin D 3 , e.g. a 7-DHC conversion of not more than 6 % results in a previtamin D 3 selectivity of at least 95 % and a 7-DHC conversion of not more than 7 % results in a previtamin D 3 selectivity of at least 94 %.
- 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 crystallization of the unreacted 7-dehydrosterol, e.g.
- 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 1 is (i) or ( ⁇ ),
- 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; provided that least one of R 2 , R 3 and R 4 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 1 is (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 (IV) above
- 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 1 ⁇ -hydroxy previtamin D 3 / l ⁇ -hydroxy vitamin D 3 (l ⁇ -hydroxycholecalciferol or alfacalcidiol); l ⁇ -hydroxy previtamin D 2 /l ⁇ -hydroxy vitamin D 2 (l ⁇ -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-
- vitamin D/previtamin D derivative of interest that can be prepared according to the present invention is calcipotriol according to formula (V) - -
- 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.
- UV LEDs in accordance with the present invention it is possible to employ a radiation source which emits almost exclusively in the optimum wavelength range for the photochemical synthesis of previtamin D 3 .
- the performance of the UV LED is comparable to the XeBr excimer type light source and it is superior to that of the presently used mercury medium-pressure lamps emitting polychromatic radiation.
- UV LEDs have a number of benefits over the XeBr excimer light source and are therefore well-suited light sources for the synthesis of previtamin D 3 on an industrial scale: They operate at low voltage and at direct current und thus there is no need for expensive high frequency power supply with necessary electromagnetic shielding as it is necessary for a XeBr excimer light source; a simple DC low voltage 5 -10 V power supply may be used for UV LEDs. This is also favorable compared to a 2-3 kV AC power supply required for a mercury medium-pressure lamp.
- UV LEDs have a very long lifetime, often more than 10.000, preferably more than 50.000 up to 100.000 h, with a constant UV power output (compared to a XeBr excimer light source suffering a 30% power loss over 1500 h and to a mercury medium-pressure lamp having a lifetime of about 10.000 h).
- the energy efficiency of UV LEDs is superior to that of XeBr excimer light sources or mercury medium-pressure lamps.
- UV LEDs can be employed in small photochemical units with a small UV power in a small reactor, e. g. for on-site on-demand production.
- UV TOP® 280 available from SENSOR ELECTRONIC TECHNOLOGY, INC. South Carolina, U. S. A
- UV TOP® 280 available from SENSOR ELECTRONIC TECHNOLOGY, INC. South Carolina, U. S. A
- the experiments are conducted in a microreactor available from Mikroglas Chemtech GmbH, Mainz,
- the microreactor is schematically depicted in Fig. 3 and consists of a quartz panel adhered to a glass panel. A small rhomboid cavity comprising an inlet and an outlet and having a height of 50 ⁇ m and a total volume of about 19 mm 3 has been etched into the glass panel.
- the experimental setup is shown in Fig. 4 and contains the described microreactor (1), the LED light source (8) with the electrical DC power supply (9) and a membrane piston pump (7) with volumetric flow rate between 45-75 ml/h at 0.6 bar pressure. The cycle loop volume is measured with 45 cm 3 . If necessary heat exchanger (4) can be used to maintain the temperature. Before the pump (7) a sample can be taken out at sample point (5). (2) and (3) designate the microreactor inlet and outlet, respectively. The 7-DHC solution may be filled in through sample point (5) and drained through drain port (6).
- the equipment is rinsed with 1-propanol, filled with 36 g 7-DHC solution and the cycling loop is started with 45 - 75 ml/h, pressure of the pump equal or lower than 0.6 bar at 26- 29°C.
- Two experiments A and B are performed and the experimental conditions thereof are shown in Table 2. Samples are taken at the times indicated in Tables 3 and 4.
- the typical reaction products previtamin D 3 and vitamin D 3 and the byproducts lumisterol and tachysterol were detected by HPLC analysis.
- the component eluting at the retention time of previtamin D 3 was positively identified as previtamin D 3 by its typical UV absorption spectrum.
- BHA tert-butyl hydroxy anisole
- T tachysterol
Abstract
The invention is directed to a photochemical process for the preparation of a previtamin D or a derivative thereof from a 7-dehydrosterol or a corresponding derivative thereof which process comprises irradiating the 7-dehydrosterol or the derivative thereof with UV LED(s).
Description
- -
PHOTOCHEMICAL PROCESS FOR THE PREPARATION OF A
PREVITAMIN D
The present invention relates to a photochemical process for the preparation of a previtamin D or a derivative thereof from a 7-dehydrosterol using UV LED(s) as UV radiation source.
It is known that previtamin D3 may be obtained from 7-dehydrocholesterol (7-DHC, provitamin D3) by irradiation with UV light. In this photochemical step the 9,10-bond of 7-DHC is cleaved to give the (Z)-triene previtamin D3. This previtamin may be converted by thermal rearrangement into vitamin D3 which is thermally more stable. Unfortunately, previtamin D3 can also absorb photons and convert to unwanted byproducts such as lumisterol and tachysterol (see Scheme 1).
Vitamin D3
Scheme 1
The quantum yields of all these photoreactions are wavelength-dependent.
Conventional photochemical synthesis of previtamin D3 on an industrial scale reportedly has been effected by irradiation of 7-DHC using mercury medium-pressure lamps. Because the starting material (7-DHC), the primary product (previtamin D3) as well as byproducts, absorb with different efficiency in the same wavelength range, polychromatic radiation of the kind supplied by these lamps favors the formation of photochemical byproducts which are inactive and in some cases toxic. Therefore, with the present state of the art, it is necessary to interrupt the irradiation after relatively low conversion of the 7- DHC to previtamin to D3. The unconverted 7-DHC is recycled while the primary product (previtamin D3) must be purified in an expensive working up procedure.
Filter effects are a further consequence of substrates and products which absorb in the same wavelength range. For example, when the absorption spectrum of previtamin D3 overlaps completely with that of 7-DHC, the previtamin absorbs a continuously increasing proportion of the light as the conversion proceeds.
Another reason for interrupting the conventional reaction after a relatively low conversion (10-20%) of 7-DHC to previtamin D3 is the fact that the quantum yield (i.e., the efficiency) of the subsequent photochemical reaction of previtamin D3 to, e.g. tachysterol, is greater than the quantum yield of the formation of the desired product (previtamin D3). Thus, in conventional reactions, the efficiency of the reaction is decreased while the cost of production of the end product is increased.
Another significant problem during conventional production of previtamin D3 is the poor correlation between the emission spectrum of mercury medium-pressure lamps and the absorption spectrum of 7-DHC. Thus, in conventional processes using mercury medium- pressure lamps only about 1% of the radiation radiating therefrom is in the desired range, i.e., between about 280 and about 300 ran, Moreover, because the radiation spectrum produced by a conventional mercury medium-pressure lamp is not optimized for the 280- 300 ran wavelength, a large amount of undesired byproducts are produced by irradiation outside this optimum wavelength region.
Similar problems exist with respect to the production of other previtamins of the vitamin D group, e.g. previtamin D2, by photolysis.
Various other sources of UV irradiation have been considered to drive the 7-DHC to previtamin D3 reaction. For example, the process of forming photons from excimer or exciplex reactions is known from laser technology. The use of excimer or exciplex lasers for the photolytic conversion of 7-DHC to previtamin D3 is described in US-A-4 388 242, EP-A-O 118 903, and Reza Kagaku Kenkyu U, 24 - 7 (1989)/Chem. Abs. JJ4, No. 9, 82251 (1991). Laser photon sources, however, are not suitable for photochemical synthesis of previtamin D3 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 D3 wherein the UV radiation source is an excimer or exciplex emitter which emits quasi- monochromatically in the UV range according to the "corona discharge" mechanism. Although the use of an incoherent excimer/exciplex light source seemed to be promising for the production of previtamin D3 the reliability of presently available excimer/exciplex light sources is insufficient for industrial application. For example, the UV power output of a XeBr lamp decreases steadily during continuous use.
Accordingly, the object of the present invention is to provide a new photolytic process for the preparation of a previtamin D, especially previtamin D3; from a 7-dehydrosterol, which process avoids the drawbacks of the prior-art procedures. The new photolytic process should be suitable for the industrial production of previtamin D3, other previtamins D and derivatives thereof on large scale.
The object is met by a photochemical process for the preparation of a previtamin D according to formula (I)
- -
or a derivative thereof from a 7-dehydrosterol according to formula (II)
or a corresponding derivative thereof,
wherein in formulae (I) and (II)
R2 is H; R3 is H; and R4 is H, CH3 or C2H5,
comprising irradiating the 7-dehydrosterol or the derivative thereof with UV light emitting diode(s) (UV LED(s)).
The present invention is further directed to a process for the preparation of a vitamin D according to formula (III)
- O -
or a derivative thereof from a 7-dehydrosterol according to formula (II) or a corresponding derivative thereof comprising preparing the previtamin D according to formula (I) or the corresponding derivative thereof as described above and further explained in detail below and converting the previtamin D or the derivative thereof to the vitamin D or the derivative thereof by thermal rearrangement.
Fig. 1 and Fig. 2 show the effect of wavelength on reaction course (DHC = 7-DHC, P = previtamin D3, T = tachysterol, and L = lumisterol).
Fig. 3 shows the microreactor used in the examples.
Fig. 4 shows the experimental setup used in the examples.
In the present invention, significantly improved levels of previtamin D production from a 7-dehydrosterol are achieved by using as the radiation source UV light emitting diode(s) (UV LED(s)). The present process is not restricted to the preparation of previtamin D3 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.
- -
Some specific provitamins, previtamins and vitamins herein involved are shown in the Table 1 below:
Table 1
The preferred previtamins and vitamins are previtamin U2/vitamin D2 and previtamin D3/vitamin D3; previtamin D3/vitamin D3 being most preferred.
A light emitting diode (LED) is a semiconductor device that emits incoherent narrow- spectrum, quasi-monochromatic light when electrically biased in the forward direction (electroluminescence). A LED is a unique type of semiconductor diode. Like a normal diode, it consists of a chip of semiconducting material impregnated, or doped, with impurities to create a p-n junction. As in other diodes, current flows easily from the p-side, or anode, to the n-side, or cathode, but not in the reverse direction. Charge-carriers - electrons and electron holes - flow into the junction from electrodes with different voltages. When an electron meets a hole, it falls into a lower energy level, and releases energy in the form of a photon. The wavelength of the light emitted, and therefore its color, depends on the band gap energy of the materials forming the p-n junction. In "ordinary" silicon or germanium diodes, the electrons and holes recombine by a non-radiative transition which produces no optical emission, because these are indirect bandgap materials. The materials used for an LED have a direct band gap with energies corresponding to near-infrared, visible or near- ultraviolet light. Typically, UV LEDs are based on (AlGaIn)N built on a sapphire substrate. However, the actual material of the UV LED is not critical for the present invention. UV LEDs suitable for the present process are, for example, commercially available form SENSOR ELECTRONIC TECHNOLOGY, INC., South Carolina, U.S.A. under the trade mark UV TOP®.
In the present process a single UV LED or a plurality of UV LEDs, for example several individual UV LEDs that are clustered into a bigger system, may be used.
It is evident form the molar absorbance spectrum of the 7-dehydrosterols, e.g. 7-DHC, that the preferred wavelength for effecting the photolysis reaction lies between 270 and 300 nm. The UV spectrum of 7-DHC shows a first dominant peak at about 282 nm and a second dominant peak at about 296 nm, those wavelengths representing the optimum wavelengths for the irradiation of 7-DHC. As all the 7-dehydrosterols have the same chromophor (the 5,7-diene system) their UV spectra are very similar. Thus, the UV LEDs for use in the present process preferably emit UV light having a wavelength between 250 and 320 nm, more preferably between 270 and 300 nm. In one embodiment of the present invention the UV LEDs emit UV light having a wavelength of 280 nm ± 10 nm.
- o -
Typically, the 7-dehydrosterol to be irradiated is dissolved in a suitable solvent. Any solvent, preferably organic solvent, that does not absorb or has low absorbency for UV radiation above 240 run and sufficiently dissolves the 7-dehydrosterol or the derivative of interest can be used. 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 1-propanol or a mixture of methanol and n- hexane. Typically, the concentration of the 7-dehydrosterol, e.g. 7-DHC, in the solvent is within the range of from 1 to 10 % by weight, preferably from 5 to 10 % by weight.
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 600C, preferably form 0 to 50°C, more preferably from 10 to 45°C, and most preferably from 25 to 45°C. An irradiation temperature within the preferred ranges is typically used in combination with the preferred solvents mentioned above.
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.
The present photochemical process may be conducted in any reactor suitable for photoreactions. The reactor design is not critical for the present invention. For example, the 7-dehydrosterol may be irradiated in a falling- film reactor, especially suitable for production of previtamin D on an industrial scale. However, it is also possible to irradiate very small amounts of the 7-dehydrosterol in a microreactor. The use of a microreactor in combination with a small UV LED enables production of small quantities of previtamin D
For example in the case of previtamin D3 preparation, 7-DHC, previtamin D3 and the unwanted byproducts lumisterol and tachysterol form a photochemical equilibrium.
- -
Theoretical calculations based on a simplified kinetic model for this system and using literature data concerning the wavelength dependency of the quantum yield and the molar absorption coefficients of the components involved lead to a graph of the concentration of each component versus reaction time. Fig. 1 shows the effect of a wavelength of 254 ran on the reaction course and is representative for radiating with a mercury medium-pressure lamp emitting a line spectrum with an intensive line at 254 nm (effect of the other emission lines omitted). Fig. 2 shows the effect of a wavelength of 282 nm on the reaction course and is representative for radiating with UV LED(s). 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. It is evident that even at high conversion of 7-DHC the theoretical selectivity for previtamin D3 is still relatively high (> 50 %) at a wavelength of 282 nm whereas tachysterol will become the main product at high conversion of 7-DHC at a wavelength of 254 nm. It is thus a significant advantage of the present process that a UV LED having the matching wavelength to favor the production of previtamin D3; even at high conversion, can be employed. Nevertheless, it may be preferred to conduct the present process at very low conversion of 7-DHC, e.g. not more than 5 %, in order to obtain a very high selectivity for previtamin D3, e.g. at least 96 %. Of course, slightly higher conversions will result in slightly lower, though still high selectivities for previtamin D3, e.g. a 7-DHC conversion of not more than 6 % results in a previtamin D3 selectivity of at least 95 % and a 7-DHC conversion of not more than 7 % results in a previtamin D3 selectivity of at least 94 %. It is within the ordinary skill of the expert involved to decide whether the process should be conducted at high or low conversion. He will weigh the advantage of very high selectivity against the disadvantage of higher costs to recycle the unreacted 7-DHC at lower conversion.
Presently available UV LEDs typically have a low UV output, e.g. about 10 mW per individual LED. The small size of an individual UV LED allows clustering into bigger systems thereby providing enough UV energy density for a commercial scale production. The still relatively low UV output of the UV LED clusters results in relatively long irradiation times that are typically used in the present process. However, it is expected that UV LEDs having a higher UV output will be available in the future, thus allowing shorter irradiation times.
In one embodiment of the present invention 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 crystallization of the unreacted 7-dehydrosterol, e.g. 7-DHC, and subsequent solid/liquid separation; 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. Typically, 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)
- -
R2 is H, a hydroxy or acyloxy group;
R3 is H, a hydroxy or acyloxy group; and
R4 is H, CH3, C2H5, a hydroxy or acyloxy group; provided that least one of R2, R3 and R4 is a hydroxy or acyloxy (ester) group.
The term "ester derivatives" or "esters" means derivatives wherein the 3-OH group is esterified with an organic acid and includes (a) previtamin D esters according to formula (IV)
R2 is H; R3 is H; R4 is H, CH3 or C2H5, and R5 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 (IV) above
R2 is H, a hydroxy or acyloxy group; R3 is H, a hydroxy or acyloxy group;
R4 is H, CH3, C2H5, a hydroxy or acyloxy group; and
R5 is an acyl group, preferably having 1 to 10 carbon atoms, e.g. acetyl and benzoyl; provided that least one of R2, R3 and R4 is a hydroxy or acyloxy (ester) group.
Examples of derivatives of previtamin D/vitamin D include 1 α-hydroxy previtamin D3/ lα-hydroxy vitamin D3 (lα-hydroxycholecalciferol or alfacalcidiol); lα-hydroxy previtamin D2/l α-hydroxy vitamin D2 (lα-hydroxyergocalciferol); 25-hydroxy previtamin D3/25-hydroxy vitamin D3 (25-hydroxycholecalciferol or calcidiol or calcifediol or Hy- D®); 25-hydroxy previtamin D2/25-hydroxy vitamin D2 (25-hydroxyergocalciferol); lα,25-dihydroxy previtamin D3/lα,25-dihydroxy vitamin D3 (lα,25- dihydroxycholecalciferol, calcitriol); lα,25-dihydroxy previtamin D2/lα,25-dihydroxy vitamin D2 (lα,25-dihydroxyergocalciferol); 1 α,24-dihydroxy previtamin D3/lα,24- dihydroxy vitamin D3 (lα,24-dihydroxycholecalciferol or tacalcitol); 24R,25-dihydroxy previtamin D3/24R,25-dihydroxy vitamin D3 (24R,25-dihydroxycholecalciferol or hydroxycalcidiol); esters thereof and esters of previtamin D2/vitamin D2 and previtamin D3/vitamin D3 themselves.
Another vitamin D/previtamin D derivative of interest that can be prepared according to the present invention is calcipotriol according to formula (V)
- -
and its corresponding previtamin. The previtamin is prepared by irradiating its corresponding provitamin.
It is a matter of fact that a specific previtamin D derivative is prepared by irradiating the corresponding derivative of the 7-dehydrosterol: For example 25-hydroxy previtamin D3 is prepared by irradiating the 25-hydroxy derivative of 7-DHC (25-hydroxy provitamin D3). Similarly, an ester of previtamin D3 is prepared by irradiating the corresponding ester derivative of 7-DHC.
Using UV LEDs in accordance with the present invention it is possible to employ a radiation source which emits almost exclusively in the optimum wavelength range for the photochemical synthesis of previtamin D3. The performance of the UV LED is comparable to the XeBr excimer type light source and it is superior to that of the presently used mercury medium-pressure lamps emitting polychromatic radiation. However, UV LEDs have a number of benefits over the XeBr excimer light source and are therefore well-suited light sources for the synthesis of previtamin D3 on an industrial scale: They operate at low voltage and at direct current und thus there is no need for expensive high frequency power supply with necessary electromagnetic shielding as it is necessary for a XeBr excimer light source; a simple DC low voltage 5 -10 V power supply may be used for UV LEDs. This is also favorable compared to a 2-3 kV AC power supply required for a mercury medium-pressure lamp. UV LEDs have a very long lifetime, often more than 10.000, preferably more than 50.000 up to 100.000 h, with a constant UV power output
(compared to a XeBr excimer light source suffering a 30% power loss over 1500 h and to a mercury medium-pressure lamp having a lifetime of about 10.000 h). The energy efficiency of UV LEDs is superior to that of XeBr excimer light sources or mercury medium-pressure lamps. UV LEDs can be employed in small photochemical units with a small UV power in a small reactor, e. g. for on-site on-demand production.
The invention will now be further illustrated in the following non-limiting example.
EXAMPLES
In the following experiments a 1 weight % solution of 7-DHC in 1 -propanol is irradiated by UV TOP® 280 (available from SENSOR ELECTRONIC TECHNOLOGY, INC. South Carolina, U. S. A) comprising 8 to 10 individual UV LEDs that are clustered together in a cone and emit UV light having a wavelength of 280 nm ± 10 nm. The experiments are conducted in a microreactor available from Mikroglas Chemtech GmbH, Mainz,
Germany. The microreactor is schematically depicted in Fig. 3 and consists of a quartz panel adhered to a glass panel. A small rhomboid cavity comprising an inlet and an outlet and having a height of 50 μm and a total volume of about 19 mm3 has been etched into the glass panel. The experimental setup is shown in Fig. 4 and contains the described microreactor (1), the LED light source (8) with the electrical DC power supply (9) and a membrane piston pump (7) with volumetric flow rate between 45-75 ml/h at 0.6 bar pressure. The cycle loop volume is measured with 45 cm3. If necessary heat exchanger (4) can be used to maintain the temperature. Before the pump (7) a sample can be taken out at sample point (5). (2) and (3) designate the microreactor inlet and outlet, respectively. The 7-DHC solution may be filled in through sample point (5) and drained through drain port (6).
All experiments are done in a dark room without daylight. The 7-DHC solution is circled through the cavity and irradiated by the LED light source through the quartz panel. The UV LED has a UV power output of about 2 mW meaning a UV flux of about 5 W/m2 at the irradiated surface. Overirradiation effects do not occur at such low UV flux. Due to the low UV flux the experiments are performed with a long irradiation time.
- -
The equipment is rinsed with 1-propanol, filled with 36 g 7-DHC solution and the cycling loop is started with 45 - 75 ml/h, pressure of the pump equal or lower than 0.6 bar at 26- 29°C. Two experiments A and B are performed and the experimental conditions thereof are shown in Table 2. Samples are taken at the times indicated in Tables 3 and 4. The typical reaction products previtamin D3 and vitamin D3 and the byproducts lumisterol and tachysterol were detected by HPLC analysis. The component eluting at the retention time of previtamin D3 was positively identified as previtamin D3 by its typical UV absorption spectrum.
Table 2: Experiments A and B, experimental conditions
Experiment A B
Circulation flow ml/h 70 45
Temperature °C 28 28
Solvent 1 -propanol 1 -propanol
[7-DHC] Wt. % 1.0 1.0
[BHA] Wt. % 0.0 0.1
BHA (tert-butyl hydroxy anisole) is a free radical scavenger that is added to minimize degradation of previtamin D3.
The following abbreviations are used in Tables 3 and 4:
DHC: 7-DHC
P: previtamin D3
D: vitamin D3
T: tachysterol
L: lumisterol conv.: conversion sel.: selectivity
- o ¬
in both experiments a significant 7-DHC conversion is reached and the obtained selectivity towards previtamin D3 and vitamin D is comparable to that of an XeBr excimer light source and superior to that of a mercury medium-pressure lamp (Hg MD lamp).
Table 3: Experiment A, results t [DHC] [P] [D] [T] [L] Sum Conv. SeI. (P+D)
(min) (wt. %) (wt. %) (wt. %) (wt. %) (wt. %) (wt. %) % %
O 0.8637 0.0014 0.8651
135 0.8471 0.0085 0.0009 0.0002 0.8567 1.12 97.92
255 0.8411 0.0187 0.0018 0.0001 0.8617 2.39 99.51
375 0.8383 0.0185 0.0023 0.8591 2.42 100.00
495 0.8279 0.0206 0.0029 0.0004 0.8518 2.81 98.33
Table 4: Expeπment B, results I
t [DHC] [P] [D] [T] [L] Sum Conv. SeI. (P+D)
(min) (wt. %) (wt. %) (wt. %) (wt. %) (wt. %) (wt. %) % %
0 0.9331 0.0013 0.0015 0.9359
170 1.0464 0.0195 0.0031 0.0002 0.0005 1.0697 2.18 97.00
290 0.8542 0.0283 0.0036 0.0003 0.8864 3.63 99.07
410 0.8330 0.0376 0.0042 0.0005 0.8753 4.83 98.82
470 0.8362 0.0416 0.0049 0.0015 0.8842 5.43 96.88
Claims
1. A photochemical process for the preparation of a previtamin D according to formula (I)
or a derivative thereof from a 7-dehydrosterol according to formula (II)
or a corresponding derivative thereof,
wherein in formulae (I) and (II)
R2 is H; R3 is H; and R4 is H, CH3 or C2H5,
comprising irradiating the 7-dehydrosterol or the derivative thereof with UV light emitting diode(s) (UV LED(s)).
2. The process according to claim 1 wherein the 7-dehydrosterol is either ergosterol or 7-dehydrocholesterol, the ergosterol being converted to previtamin D2 and the 7- dehydrocholesterol being converted to previtamin D3.
3. The process according to claim 2 wherein the 7-dehydrosterol is 7- dehydrocholesterol that is converted to previtamin D3.
4. The process according to claim 1 wherein the derivative of a previtamin D is an ester of a previtamin D or is a derivative according to formula (I) wherein R1, R , R3 and R4 are defined as in claim 1 with the modification that at least one of R , R3 and R4 is a hydroxy or acyloxy group.
5. The process according to claim 1 wherein the derivative of a previtamin D is selected from the group consisting of previtamin of calcipotriol, lα-hydroxy previtamin D3, lα-hydroxy previtamin D2; 25 -hydroxy previtamin D3, 25 -hydroxy previtamin D2, lα,25-dihydroxy previtamin D3, lα,25-dihydroxy previtamin D2,
1 α,24-dihydroxy previtamin D3, 24R,25-dihydroxy previtamin D3, acyloxy previtamin D3, esters thereof and esters of previtamin D2 and D3.
6. The process according to claim 5 wherein the derivative of a previtamin D is 25- hydroxy previtamin D3.
7. The process according to any of the preceding claims wherein the UV LED(s) emit UV light having a wavelength between 270 and 300 nm.
8. The process according to any of the preceding claims wherein the irradiation is performed in a falling-film reactor.
9. The process according to any of the preceding claims further comprising recovering the previtamin D or the derivative thereof.
10. A process for the preparation of a vitamin D according to formula (III)
or a derivative thereof from a 7-dehydrosterol according to formula (II)
or a corresponding derivative thereof comprising preparing the previtamin D according to formula (I)
or the corresponding derivative thereof, wherein in formulae (I), (II) and (III)
R2 is H; R3 is H; and R4 is H, CH3 or C2H5,
according to the process of any of claims 1 to 9 and converting the previtamin D or the derivative thereof to the vitamin D or the derivative thereof by thermal rearrangement.
***
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP07008307 | 2007-04-24 | ||
EP07008307.6 | 2007-04-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2008128783A2 true WO2008128783A2 (en) | 2008-10-30 |
WO2008128783A3 WO2008128783A3 (en) | 2008-12-24 |
Family
ID=39876008
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2008/003321 WO2008128783A2 (en) | 2007-04-24 | 2008-04-24 | Photochemical process for the preparation of a previtamin d |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN101668739A (en) |
WO (1) | WO2008128783A2 (en) |
Cited By (10)
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 |
CN102850248A (en) * | 2012-09-29 | 2013-01-02 | 浙江花园生物高科股份有限公司 | Technology for preparing vitamin D3 |
JP2016523934A (en) * | 2014-06-04 | 2016-08-12 | 正源堂(天津▲濱▼海新区)生物科技有限公司 | Ergosterol compounds and methods for producing and using the same |
KR20170096159A (en) * | 2014-12-18 | 2017-08-23 | 누셀리스 엘엘씨 | Methods for improved production of vitamins d2 and d3 |
JP2018528944A (en) * | 2015-09-25 | 2018-10-04 | コンテクスト バイオファーマ インコーポレイテッド | Method for producing onapristone intermediate |
US10548905B2 (en) | 2015-12-15 | 2020-02-04 | Context Biopharma Inc. | Amorphous onapristone compositions and methods of making the same |
US10786461B2 (en) | 2014-11-17 | 2020-09-29 | Context Biopharma Inc. | Onapristone extended-release compositions and methods |
WO2020230159A1 (en) * | 2019-05-10 | 2020-11-19 | Fermenta Biotech Limited | Irradiation process of pro vitamin d |
US11613555B2 (en) | 2016-11-30 | 2023-03-28 | Context Biopharma, Inc. | Methods for onapristone synthesis dehydration and deprotection |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111960980A (en) * | 2019-05-20 | 2020-11-20 | 重庆桑禾动物药业有限公司 | Method for synthesizing pre-vitamin D3 by using LED ultraviolet lamp |
CN112110841B (en) * | 2019-06-21 | 2022-12-06 | 重庆桑禾动物药业有限公司 | Method for synthesizing vitamin D3 by segmenting and determining spectral bands |
CN110790807B (en) * | 2019-11-04 | 2021-08-06 | 广西师范大学 | Method for preparing 9 beta, 10 alpha-dehydroprogesterone diethyl ketal by using LED light source |
CN110713449A (en) * | 2019-11-12 | 2020-01-21 | 广西师范大学 | Efficient green production process of vitamin D3 |
CN110818760B (en) * | 2019-11-12 | 2021-06-25 | 广西师范大学 | Production process capable of industrially synthesizing dydrogesterone |
CN110724081B (en) * | 2019-11-12 | 2023-08-15 | 广西师范大学 | Efficient production process of vitamin D2 |
CN111116442A (en) * | 2020-01-03 | 2020-05-08 | 宁波东隆光电科技有限公司 | Preparation method of vitamin D |
CN111171101B (en) * | 2020-01-03 | 2023-04-11 | 宁波东隆智能科技有限公司 | Preparation method of dydrogesterone intermediate |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0118903A1 (en) * | 1983-03-10 | 1984-09-19 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Photochemical process for the preparation of previtamin D2 and D3 starting from ergosterol or 7-dehydro cholesterol |
EP0967202A1 (en) * | 1998-06-23 | 1999-12-29 | F. Hoffmann-La Roche Ag | Photolysis of 7-dehydrocholesterol |
US20050042743A1 (en) * | 2002-07-11 | 2005-02-24 | Chihiro Kawai | Porous semiconductor and process for producing the same |
WO2006126482A1 (en) * | 2005-05-26 | 2006-11-30 | Matsushita Electric Industrial Co., Ltd. | Refrigerator |
DE102006022004A1 (en) * | 2006-05-10 | 2007-11-15 | Heraeus Noblelight Gmbh | Fluid treatment plant, in particular water disinfection plant |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2266761C2 (en) * | 2003-10-24 | 2005-12-27 | Марков Валерий Николаевич | All-purpose compact light-emitting diode-based radiator usable in preventing and treating diseases |
-
2008
- 2008-04-24 WO PCT/EP2008/003321 patent/WO2008128783A2/en active Application Filing
- 2008-04-24 CN CN200880013359A patent/CN101668739A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0118903A1 (en) * | 1983-03-10 | 1984-09-19 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Photochemical process for the preparation of previtamin D2 and D3 starting from ergosterol or 7-dehydro cholesterol |
EP0967202A1 (en) * | 1998-06-23 | 1999-12-29 | F. Hoffmann-La Roche Ag | Photolysis of 7-dehydrocholesterol |
US20050042743A1 (en) * | 2002-07-11 | 2005-02-24 | Chihiro Kawai | Porous semiconductor and process for producing the same |
WO2006126482A1 (en) * | 2005-05-26 | 2006-11-30 | Matsushita Electric Industrial Co., Ltd. | Refrigerator |
DE102006022004A1 (en) * | 2006-05-10 | 2007-11-15 | Heraeus Noblelight Gmbh | Fluid treatment plant, in particular water disinfection plant |
Non-Patent Citations (3)
Title |
---|
BRAUN M ET AL: "Improved photosynthesis of previtamin D by wavelengths of 280-300 nm" JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY, A: CHEMISTRY, CHELSEVIER SEQUOIA, LAUSANNE, vol. 61, no. 1, 1 January 1991 (1991-01-01), pages 15-26, XP002499729 * |
DATABASE EPODOC EUROPEAN PATENT OFFICE, THE HAGUE, NL; RU2266761 27 December 2005 (2005-12-27), MARKOV ET AL: "All-purpose compact Light emitting diode-based radiator usable in preventing and treating diseases" XP002502257 & RU 2 266 761 C2 27 December 2005 (2005-12-27) * |
TERENETSKAYA I P ET AL: "Analysis of the two-stage irradiation of provitamin D taking into account the irreversible photoreactions of previtamin" PHARMACEUTICAL CHEMISTRY JOURNAL, USCONSULTANTS BUREAU, NEW YORK, NY, vol. 27, no. 11, 1 January 1993 (1993-01-01), pages 797-803, XP002499730 * |
Cited By (21)
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 |
CN102850248A (en) * | 2012-09-29 | 2013-01-02 | 浙江花园生物高科股份有限公司 | Technology for preparing vitamin D3 |
JP2016523934A (en) * | 2014-06-04 | 2016-08-12 | 正源堂(天津▲濱▼海新区)生物科技有限公司 | Ergosterol compounds and methods for producing and using the same |
US11672762B2 (en) | 2014-11-17 | 2023-06-13 | Context Biopharma, Inc. | Onapristone extended-release compositions and methods |
US10786461B2 (en) | 2014-11-17 | 2020-09-29 | Context Biopharma Inc. | Onapristone extended-release compositions and methods |
JP2018501262A (en) * | 2014-12-18 | 2018-01-18 | ヌセリス エルエルシー | Process for producing improved vitamins D2 and D3 |
JP7193521B2 (en) | 2014-12-18 | 2022-12-20 | チーブス ヨーロッパ ベー.フェー. | Method for producing improved vitamins D2 and D3 |
KR102331419B1 (en) * | 2014-12-18 | 2021-11-26 | 시버스 유럽 비.브이. | Methods for improved production of vitamins d2 and d3 |
JP2021059577A (en) * | 2014-12-18 | 2021-04-15 | チーブス ヨーロッパ ベー.フェー. | Method for improved production of vitamins d2 and d3 |
KR20170096159A (en) * | 2014-12-18 | 2017-08-23 | 누셀리스 엘엘씨 | Methods for improved production of vitamins d2 and d3 |
US10988443B2 (en) | 2014-12-18 | 2021-04-27 | Nucelis Llc | Methods for improved production of vitamins D2 and D3 |
JP2021120396A (en) * | 2015-09-25 | 2021-08-19 | コンテクスト バイオファーマ インコーポレイテッド | Methods of making onapristone intermediates |
US10308676B2 (en) | 2015-09-25 | 2019-06-04 | Context Biopharma Inc. | Methods of making onapristone intermediates |
EP3353148A4 (en) * | 2015-09-25 | 2019-04-24 | Context Biopharma Inc. | Methods of making onapristone intermediates |
JP2018528944A (en) * | 2015-09-25 | 2018-10-04 | コンテクスト バイオファーマ インコーポレイテッド | Method for producing onapristone intermediate |
US10548905B2 (en) | 2015-12-15 | 2020-02-04 | Context Biopharma Inc. | Amorphous onapristone compositions and methods of making the same |
US11613555B2 (en) | 2016-11-30 | 2023-03-28 | Context Biopharma, Inc. | Methods for onapristone synthesis dehydration and deprotection |
WO2020230159A1 (en) * | 2019-05-10 | 2020-11-19 | Fermenta Biotech Limited | Irradiation process of pro vitamin d |
EP3965774A4 (en) * | 2019-05-10 | 2023-10-11 | Fermenta Biotech Limited | Irradiation process of pro vitamin d |
Also Published As
Publication number | Publication date |
---|---|
WO2008128783A3 (en) | 2008-12-24 |
CN101668739A (en) | 2010-03-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2008128783A2 (en) | Photochemical process for the preparation of a previtamin d | |
Fuse et al. | Continuous-flow synthesis of vitamin D 3 | |
US4686023A (en) | Sensitized photochemical preparation of vitamin D | |
EP0077353A1 (en) | 1-hydroxylation process | |
IL268784A (en) | Process for preparing bromotrichloromethane | |
JP7193521B2 (en) | Method for producing improved vitamins D2 and D3 | |
Meyerson et al. | Organic Ions in the Gas Phase. XVII. A Bicyclic Doubly Hydrogen-Bridged Transition State in Decomposition of 6-Substituted Alkanoic Acids and Esters | |
WO2008128782A2 (en) | Photochemical process for the preparation of a previtamin d | |
US6180805B1 (en) | Photochemical process for the production of previtamin D3 | |
WO2021005619A1 (en) | Improved, cost effective process for synthesis of vitamin d3 and its analogue calcifediol from ergosterol | |
TW201400443A (en) | Method for producing cycloalkanone oxime | |
EP0152138B1 (en) | Method of preparing 9beta,10alpha-5,7-diene-steroids | |
GB2217716A (en) | Vitamin d homologs | |
Noël et al. | Industrial photochemistry: from laboratory scale to industrial scale | |
US6660132B1 (en) | Photochemical and thermochemical solar syntheses using flat-bed solar collectors/solar reactors | |
Kocienski et al. | New routes to 1α-hydroxyvitamin D3 | |
CN117105741A (en) | Method for photocatalytic isomerization of alkine alcohol | |
SATO et al. | EFFECT OF WAVELENGTH ON THE FORMATION OF 1α-HYDROXYPREVITAMIN D3 IN THE ULTRAVIOLET IRRADIATION OF CHOLESTA-5, 7-DIENE-1α, 3β-DIOL AND USE OF A FILTER SOLUTION IN THE PHOTOCHEMICAL REACTION IN THE SYNTHESIS OF 1 α-HYDROXY-VITAMIN D3 | |
Vanmaele et al. | lα-hydroxy previtamin D3, and its selective formation from 1-keto previtamin D3 | |
Tinnemans et al. | Photocyclisations of 1, 4-diarylbut-1-en-3-ynes. Part II. Mechanism of the reaction | |
EP2225193B1 (en) | Photochemical isomerization of a pent-2-en-4-yn-1-ol | |
KR20220018541A (en) | Isomerization of Polyunsaturated Non-Aromatic Compounds | |
HU201723B (en) | Process for producing 5-bromo-1-pentanal or its acetal derivatives formed with monohydric or dihydric alcohols having 1-5 carbon atoms | |
JPS5923304B2 (en) | Production method of vitamin D↓3 | |
Kaneko et al. | Synthesis and biological activity of 2α-hydroxyvitamin D 3 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200880013359.5 Country of ref document: CN |
|
NENP | Non-entry into the national phase in: |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 7320/DELNP/2009 Country of ref document: IN |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 08749113 Country of ref document: EP Kind code of ref document: A2 |