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 at low conversion of 7- dehydrosterol.

It is known that 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).

Dehydrocholesterol

Vitamin D3

Scheme 1

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. Similar problems exist with respect to the production of other previtamins of the vitamin D group, e.g. previtamin D ₂ , by photolysis. Thus, it was known that irradiating the starting material (7-DHC) until a high conversion of 7-DHC is reached is detrimental for the purity of the primary product (previtamin D ₃ ). Accordingly, the total conversion of 7-DHC was generally kept below 50 %, preferably between 30 and 40 %. Nevertheless, all prior efforts to improve the irradiation process are focused on achieving a maximum total conversion of the starting material (7-DHC) while at the same time keeping the amount of unwanted byproducts (e.g. lumisterol and tachysterol) at a tolerable level. The approaches to reach this goal are diverse, most of the scientists endeavor to find the optimum wavelength that would bring high selectivity towards previtamin D ₃ at high conversion.

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, however, 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 %.

Although the use of an incoherent excimer/exciplex light source seemed to be promising for the production of previtamin D ₃ 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.

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. In both references 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. However, double irradiation requires additional reaction equipment and increases production costs.

Accordingly, 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.

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)

R ² is H; R ³ is H; and R ⁴ is H, CH ₃ or C ₂ H ₅ ,

comprising irradiating the 7-dehydrosterol or the derivative thereof with UV light until a maximum conversion of 7-dehydrosterol or the derivative thereof of less than 12 % is reached.

The present invention is further directed to a process for the preparation of a vitamin D according to formula (III)

(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 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 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.

In the present invention 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. Preferably, the 7-dehydrosterol is irradiated until a maximum conversion of 10 % or less than 10 % is reached. In some embodiments, 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.

Typically 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. However, 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. For example, 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. Of course, the actual selectivity achievable in a real reaction system is always lower than the theoretical values.

For economical reasons, 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. Examples of 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.

Some specific provitamins, previtamins and vitamins herein involved are shown in the Table 1 below:

Table 1

R in formula (I) and R = H

The preferred previtamins and vitamins are previtamin D ₂ /vitamin D ₂ and previtamin D ₃ /vitamin D ₃ ; previtamin D ₃ /vitamin D ₃ being most preferred.

It is evident form the molar absorbance spectrum of the 7-dehydrosterols, e.g. 7-DHC, that the optimal wavelength for effecting the photolysis reaction lies between 270 and 300 run. As all the 7-dehydrosterols have the same chromophor (the 5,7-diene system) their UV spectra are very similar.

In a preferred embodiment, 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. If the present process is conducted batchwise, 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.

Typically, 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 costs for separating and recycling the unconverted 7-dehydrosterol increase with decreasing selectivity and increasing conversion. It is within the ordinary skill of the expert involved to decide at which conversion a process should be conducted. He will weigh the advantages of very high selectivity against the disadvantage of higher costs to separate and recycle the unreacted 7-dehydrosterol at lower 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.

In another embodiment of the present invention using a XeBr excimer lamp (or any other light source emitting light at the optimum wavelength and showing a very weak dependence of the selectivity on the conversion the loss in selectivity at higher conversion is almost equal to the saving in recycling costs. Thus, the break even point is reached at about 10 % conversion using the same recycling system.

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 nm 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 a mixture of methanol and n-hexane, preferably in a volume ratio of 2:1. Typically, 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. In a preferred embodiment 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.

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. In case the 7-dehydrosterol is dissolved in a mixture of methanol and n-hexane 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.

For example, the 7-dehydrosterol may be irradiated in a falling-film reactor, especially suitable for production of previtamin D on an industrial scale. In case a single irradiation does not result in the desired conversion 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.

In a preferred embodiment of the present process, the separation of the 7-dehydrosterol in step (b) involves at least one, preferably at least two, more preferably two crystallization steps. In 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. In a more preferred embodiment, a distilling step is performed between the first and second crystallization steps. In the distilling 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.

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. In the distillation step, most of the n-hexane, preferably the total n-hexane, is removed from the methanol. During the distillation 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. 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. One 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. However, 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. Generally, 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.

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 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)

wherein R is (ϋ), 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.

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)

R ⁴ R ⁴

wherein 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

(IV) above

wherein R is (ii),

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; and 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 lα-hydroxy previtamin D ₃ /lα-hydroxy vitamin D ₃ (lα-hydroxycholecalciferol or alfacalcidiol); lα-hydroxy previtamin D ₂ /l α-hydroxy vitamin D ₂ (1 α-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); lα,25-dihydroxy previtamin D ₃ /lα,25-dihydroxy vitamin D ₃ (lα,25- dihydroxycholecalciferol, calcitriol); lα,25-dihydroxy previtamin D ₂ /lα,25-dihydroxy vitamin D ₂ (lα,25-dihydroxyergocalciferol); 1 α,24-dihydroxy previtamin D ₃ /lα,24- dihydroxy vitamin D ₃ (lα,24-dihydroxycholecalciferol or tacalcitol); 24R,25-dihydroxy previtamin D ₃ /24R,25-dihydroxy vitamin D ₃ (24R,25-dihydroxycholecalciferol or hydroxycalcidiol); esters thereof and esters of previtamin D ₂ /vitamin D ₂ and previtamin D ₃ /vitamin D ₃ 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 D ₃ is prepared by irradiating the 25-hydroxy derivative of 7-DHC (25-hydroxy provitamin D ₃ ). Similarly, an ester of previtamin D ₃ is prepared by irradiating the corresponding ester derivative of 7-DHC.

The invention will now be further illustrated in the following non-limiting examples.

EXAMPLES

Description of flow diagrams depicted in Fig. 3, 4 and 5:

Fig. 3:

1. Solvent A Feed solution tank

2. Provitamin B Photo irradiation reactor

3. Provitamin solution C UV light source

4. Irradiated solution (recycle) D Power supply

5. Irradiated solution (final)

Fig. 4:

1. Solvent A Feed solution tank

2. Provitamin B Photo irradiation reactor

3. Provitamin solution C UV light source 5. Irradiated solution D Power supply

E Irradiated solution tank

Fig. 5:

5. Irradiated solution F First Crystallizer

6. First provitamin slurry G First solid/liquid separation

7. First wash liquid H Distillation unit

8. First wet cake of pro vitamin I Distillate collector

9. First mother liquor J Second Crystallizer

10. Distillate K Second solid/liquid separation

11. Provitamin solution

12. Second provitamin slurry

13. Second wash liquid

14. Second wet cake of provitamin

15. Second mother liquor

Example 1

In this example the 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 %.

Example 2

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). 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.

Conversion of 7-DHC: 7.8 %; selectivity for previtamin D ₃ : 96.0 %.

Example 3

In this example 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. After 7 passes the irradiated solution (5) was analyzed with HPLC

Conversion of 7-DHC: 8.4 %; selectivity for previtamin D ₃ : 86.7 %.

Example 4

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 %.

Example 5

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. 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. After 3 passes 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.

Conversion of 7-DHC: 10.7 %; selectivity for previtamin D ₃ : 93.5 %.

Example 6

In this example the reaction set-up as shown in Fig. 4 in combination with separation setup shown in Fig. 5 was used. 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). At -20°C 7-DHC crystallized. 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.