CN101663269A - Photochemical process for the preparation of a previtamin d - Google Patents
Photochemical process for the preparation of a previtamin d Download PDFInfo
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- CN101663269A CN101663269A CN200880013040A CN200880013040A CN101663269A CN 101663269 A CN101663269 A CN 101663269A CN 200880013040 A CN200880013040 A CN 200880013040A CN 200880013040 A CN200880013040 A CN 200880013040A CN 101663269 A CN101663269 A CN 101663269A
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- 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
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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 comprisesirradiating 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.
Description
The present invention relates to a kind of photochemical method of under the low-conversion of 7-dehydrogenation sterol, making provitamin D or derivatives thereof by 7-dehydrogenation sterol.
Known provitamin D
3Can be by 7-aphyllidine (7-DHC, pro-vitamin D
3) obtain by the UV optical radiation.In this photochemical step, 9 of 7-DHC, thus the 10-bond cleavage is separated and is obtained (Z)-triolefin provitamin D
3This provitamin can change into more heat-staple vitamins D by thermal rearrangement
3Unfortunately, provitamin D
3Can also absorb photon and change into undesirable by product, such as lumisterol and tachysterol (referring to synoptic diagram 1).
Synoptic diagram 1
Reported the provitamin D on the technical scale
3Conventional photochemistry synthetic by adopting medium pressure mercury lamp that 7-DHC is shone realization.Because raw material (7-DHC), primary product (provitamin D
3) and the assimilated efficiency difference of by product in same wavelength region, help formation nonactive and deleterious in some cases photochemistry by product so be derived from the polychromatic radiation of this lamp.Similar problem is present in other provitamins (the provitamin D for example that produces vitamins D family by photodissociation
2) method in.Therefore, irradiation raw material (7-DHC) up to the high conversion that obtains 7-DHC to primary product (provitamin D
3) purifying harmful.Therefore, the total conversion rate of 7-DHC remains on below 50% usually, preferably between 30 and 40%.Yet the past, all effort that improve illuminating method all concentrated on: make the total conversion rate of raw material (7-DHC) the highest, make the amount of undesirable by product (for example lumisterol and tachysterol) remain on tolerable level simultaneously.The method that realizes this target is diversified, and most of scientists strive to find and can make provitamin D
3The optimal wavelength that transformation efficiency is higher and selectivity is higher.
EP-A-0118 903 has described by laser and has shone 7-DHC with 50% transformation efficiency, and this laser emission wavelength is in or approaching 9 of the raw material, the monochromatic UV light of 10-key photochemistry cracked optimal values of making.The provitamin D that is reported
3Selectivity be at least 80%.Yet the laser optical component is unsuitable for the synthetic provitamin D of technical scale photochemistry
3, because their technical complexity is very high and because their radiation geometrical shape is unsuitable for preparation property photochemistry and relevant therewith radiation density deficiency on big zone.
EP-A-0967 202 discloses a kind of transformation efficiency with 50% and has produced provitamin D
3Photochemical method, wherein, the UV source of radiation is according to " corona discharge " mechanism excite state molecule or exciplex projector with the monochromatic mode of standard (quasi-monochromatically) emission in best UV scope.The provitamin D that is reported
3Selectivity be about 93%.Although as if incoherent excite state molecule/exciplex light source be hopeful to be used to produce provitamin D
3, but can get reliability deficiency for industrial application of excite state molecule/exciplex light source at present.For example, between the continuous usage period, the UV power output steady decrease of XeBr lamp.
US-A-4,388,242 and US-A-4,686,023 have described with the irradiation of two steps and have produced provitamin D
3(or D
2) method, wherein, in first irradiating step, 7-DHC mainly changes into the provitamin D of minor amount
3With the tachysterol of main amount, the tachysterol of main amount changes into provitamin D in second irradiating step then
3In these two pieces of reference, first irradiating step is carried out under higher 7-DHC transformation efficiency, and for example by US-A-4, the transformation efficiency of 686,023 example calculation is greater than 90%.Yet the irradiation of two steps needs extra conversion unit and has increased production cost.
Therefore, the object of the present invention is to provide and a kind ofly prepare provitamin D (provitamin D especially by 7-dehydrogenation sterol
3) novel photolytic process, described method makes the amount of undesirable by product lower, avoids using complicated multistep irradiation and need not use expensive UV light source.This novel photolytic process should be suitable for large-scale commercial production provitamin D
3With other provitamin D.
This purpose realizes by a kind of provitamin D of the 7-dehydrogenation sterol or derivatives thereof preparation formula (I) by formula (II) or the photochemical method of its corresponding derivative:
Wherein in formula (I) and formula (II),
R
1Be
R
2Be H; R
3Be H; R
4Be H, CH
3Or C
2H
5,
Described method comprises: adopt UV rayed 7-dehydrogenation sterol or derivatives thereof, up to the maximum conversion rate that is less than less than 12% 7-dehydrogenation sterol or derivatives thereof.
The invention further relates to by the vitamins D of the 7-dehydrogenation sterol or derivatives thereof preparation formula (III) of formula (II) or the method for its corresponding derivative,
Described method comprises:
As mentioned above and as detailed below provitamin D or its corresponding derivative of preparation formula (I); And
Make provitamin D or derivatives thereof change into the vitamins D or derivatives thereof by thermal rearrangement.
Fig. 1 is the irradiation of having described under the 254nm wavelength, provitamin D
3Selectivity and the figure line of the relation of the transformation efficiency of 7-DHC.
Fig. 2 is the irradiation of having described under the 282nm wavelength, provitamin D
3Selectivity and the figure line of the relation of the transformation efficiency of 7-DHC.
Fig. 3 is the schema of the irradiation process described in embodiment 1 and 2.
Fig. 4 is the schema of the irradiation process described in embodiment 3,4,5 and 6.
Fig. 5 is the schema of separating technology described in the embodiment 6.
In the present invention, under low-conversion, prepare provitamin D or derivatives thereof with high selectivity, Be that the maximum conversion of raw material 7-dehydrogenation sterol is less than 12%. Preferably, irradiation 7-dehydrogenation sterol is straight Reach 10% or less than 10% maximum conversion rate. In some embodiments, irradiation 7-dehydrogenation steroid Alcohol is until reach 7% or less than 7% maximum conversion rate, in other embodiments, irradiation 7-goes The hydrogen sterol is until reach about 5% maximum conversion rate.
Irradiation is until reach a certain maximum conversion rate and mean: photochemistry technology is to avoid more high conversion Mode carry out. For example, irradiation is until be less than 12% conversion ratio and mean: avoid conversion ratio Be 12% or higher. In batch technology, this means under less than 12% conversion ratio to stop this light Chemical technology; In continuous processing, thereby this means that average retention time is adjusted to enough weak points protects Hold the low conversion rate of this technology in 12%. Corresponding statement also can be applicable to above-mentioned other maximum conversion Rate.
Usually, the selective of provitamin D or derivatives thereof is at least 80%; In some enforcement sides In the formula, be at least 85%; In other embodiments, be at least 90%; At other embodiments In, be at least 95%.
The theory of the provitamin D or derivatives thereof that can realize selectively depends on conversion ratio and irradiation Used UV light wavelength. The inventor is according to the 7-DHC photochemical transformation is become provitamin D3With The dynamic model of undesirable by-product lumisterin and tachysterol (referring to schematic diagram 1) is counted Calculate. Consider that the mole of the wavelength dependence of related quantum yield and related each component absorbs Coefficient can be described selective and conversion ratio dependence, Fig. 1 and Fig. 2 respectively for 254nm with The illumination wavelength of 282nm. Obviously found out by upper figure, under two wavelength to provitamin D3Choosing Selecting property reduces along with the increase of conversion ratio. Yet, in the feelings of the optimal wavelength of about 282nm irradiation Under the condition, the gradient of decline is not steep, this means: irradiation process can be under relatively high conversion ratio Carry out, still obtain the high selectivity to provitamin D or derivatives thereof. Wavelength at about 296nm In the situation of (it is equivalent to second main peak in the 7-DHC absorption spectrum) irradiation, obtain the figure of type Shape. If under not good wavelength (for example 254nm), shine, must be in relatively low turning to Interrupt irradiation under the rate, thereby realize rational high selectivity. For example, 10% conversion ratio causes Theory under 282nm or the 296nm selectively is higher than 95%, and under 254nm selectively only is About 85%. Certainly, obtainable actual selection always is lower than theoretical value in the reaction system of reality According to.
For consideration economically, preferably shine 7-dehydrogenation sterol until reach at least 2% conversion Rate.
Photochemical method of the present invention is not limited to the UV radiation source of any particular type. Available The example of UV radiation source comprise emission wavelength between 270 and 300nm between the accurate monochromatic UV of light Radiation source, for example XeBr or Br2Excimer lamp; Some laser is such as excite state molecular laser or sharp Attitude compound laser; With UV LED; And polychrome UV radiation source, such as the emission line spectrum The standard medium pressure mercury lamp of (have strong line under 254nm, this is not best wavelength).
Method of the present invention is not limited to prepare provitamin D3, can also decide for the preparation of previous Various compounds (comprising derivative) in the vitamin D family of justice are because all provitamins (7-dehydrogenation sterol) has identical 4-ring steroid class skeleton, wherein has two in 5-position and 7-position Two keys (steroid 5,7-diene), this 5, the 7-diene structure determines the photochemistry behavior of these compounds.
Related some concrete provitamins, provitamin and the vitamin of this paper is listed in the following table 1:
Table 1
R in the formula (I)2And R3＝H
Mole absorption spectrum by 7-dehydrogenation sterol (for example DHC) can be known and knows, produces photodissociation The reaction optimal wavelength between 270 and 300nm between. Because all 7-dehydrogenation sterols all have Identical chromophore (5,7-diene system) is so their UV spectrum is very similar.
In preferred embodiment, the method according to this invention also comprises following additional step except irradiating step (a): (b) the unconverted 7-dehydrogenation of near small part sterol or derivatives thereof is separated from reaction mixture.More preferably, present method further comprises following step afterwards: (c) with the separate part cycle applications of unconverted 7-dehydrogenation sterol in irradiating step (a).
The unconverted 7-dehydrogenation of cycle applications sterol has improved the economic feasibility of present method.If method of the present invention is intermittently carried out, with unconverted 7-dehydrogenation sterol cycle applications at least once, preferred cycle is used repeatedly so, more preferably at least 15 times, and most preferably at least 20 times.In preferred embodiment, present method is carried out continuously, and it comprises the unconverted 7-dehydrogenation of continuous cycle applications sterol.
Usually, with at least 90%, preferred at least 95%, more preferably at least 98%, most preferably at least 99% unconverted 7-dehydrogenation sterol is separated from reaction mixture and cycle applications in irradiating step.
Along with the optionally rising of reduction and transformation efficiency, the cost that is used to separate with the unconverted 7-dehydrogenation of cycle applications sterol also increases.Determine that method of the present invention should be those skilled in the art's a common skill under what kind of transformation efficiency.They will weigh the very advantage and the inferior position that reclaims unreacted 7-DHC (than low-conversion) higher cost of highly selective.
In an embodiment of the invention (the use medium pressure mercury lamp shines and selectivity has very strong dependency to transformation efficiency), the transformation efficiency about 5% reaches wherein cost recovery and the selectivity income reaches the equilibrated breakeven point.
In another embodiment of the present invention (XeBr excimer lamp (or other light source) arbitrarily and the selectivity of using emission to have optimal wavelength light have very weak dependency to transformation efficiency), the selectivity loss under high conversion more is equivalent to the surplus of cost recovery basically.Therefore, use the identical recycle system, be issued to breakeven point at about 10% transformation efficiency.
Usually, 7-dehydrogenation sterol to be illuminated is dissolved in the appropriate solvent.Can use and anyly can not absorb the above UV radiation of 240nm or the UV radiation more than the 240nm is had low absorptivity and fully the 7-dehydrogenation sterol paid close attention to of dissolving or the solvent of derivative, preferred organic solvent.Example comprises lower alcohol, such as methyl alcohol, ethanol and 1-propyl alcohol; Simple ether is such as diethyl ether; Cyclic ether, such as tetrahydrofuran (THF) and 1, the 4-dioxane; Asymmetrical ether is such as t-butyl methyl ether; Alkane, such as normal hexane, and composition thereof.The preferred solvent that is used for 7-dehydrogenation sterol (especially 7-DHC) is changed into provitamin D is the mixture of methyl alcohol and normal hexane, preferably with the methyl alcohol of 2: 1 volume ratios and the mixture of normal hexane.Usually, the concentration of 7-dehydrogenation sterol (for example 7-DHC) in solvent is in the scope of 1 to 15 weight %, preferably in the scope of 5 to 10 weight %.In preferred embodiment, 7-dehydrogenation sterol is dissolved in the mixture of methyl alcohol and normal hexane with the concentration of 7-10 weight %.
Irradiation can be at free-radical scavengers, tertiary butyl hydroxyanisol (BHA) for example, existence under carry out, thereby make the minimum degradation of provitamin D.
Irradiation temperature can not influence photochemical reaction.Generally speaking, the selected so that 7-dehydrogenation sterol of temperature is dissolved in the solvent for use.According to the type of solvent for use and specific 7-dehydrogenation sterol, irradiation usually in-20 to 60 ℃ of scopes, preferably in 0 to 50 ℃ of scope, more preferably in 10 to 45 ℃ of scopes, most preferably carry out under the temperature in 25 to 45 ℃ of scopes.Under 7-dehydrogenation sterol was dissolved in situation in methyl alcohol and the normal hexane mixture, the representative temperature scope that is used to shine was 0 to 60 ℃, is preferably 10 to 50 ℃, more preferably 20 to 45 ℃, even more preferably 30 to 45 ℃, most preferably be 35 to 45 ℃.
Photochemical method of the present invention can be suitable for photoresponse arbitrarily and provide enough irradiating surfaces (to this means UV power density W/m
2Enough low) reactor in carry out.DESIGN OF REACTOR has no importance for the present invention, and selecting suitable reactor design is this area scientist's common skill.
For example, 7-dehydrogenation sterol can especially shine in the falling film reactor that is suitable for industrial-scale production provitamin D in falling film reactor.Can not obtain at single fraction irradiation under the situation of required transformation efficiency, can reirradiation once or several times up to reaching required transformation efficiency.Can realize reirradiation with intermittent mode or continuous mode by following: make 7-dehydrogenation sterol solution circulated pass through falling film reactor.
In the preferred implementation of the inventive method, in step (b), separate 7-dehydrogenation sterol and comprise: at least one, preferably at least two, more preferably two crystallisation steps.In crystallisation step, be precipitated out from solvent by cooling off the unreacted 7-dehydrogenation of near small part sterol usually; Then the 7-dehydrogenation sterol that is settled out is passed through solid/liquid separation, for example, preferably, from solvent, separate by centrifugal by centrifugal or filtration; At last 7-dehydrogenation sterol is circulated back in the irradiation step.In preferred embodiment, between first crystallisation step and second crystallisation step, carry out distilation steps.In distilation steps, remove partial solvent at least, thereby promote the precipitation of 7-dehydrogenation sterol.(should avoid too early isomery to form vitamins D) because provitamin D and should not be converted to unknown product do not wish but the temperature sensitivity of limited by product is preferably carried out distilation steps, thereby is avoided high temperature under mild conditions (i.e. decompression).
The inventor finds, the mixture of methyl alcohol and normal hexane, and preferred volume ratio is that 2: 1 the methyl alcohol and the mixture of normal hexane are the preferred solvent that is used for sepn process, described sepn process comprises two crystallisation steps and a middle distilation steps.In distilation steps, from methyl alcohol, remove most of normal hexane, preferably remove whole normal hexanes.During distilling, 7-dehydrogenation sterol begins by solution crystallization, if concentration of slurry is too high, needs to add some extra methyl alcohol so." solvent switch " of carrying out during distillating carbinol/hexane solution also can be applicable to other solvent system.
To be circulated back to by the 7-dehydrogenation sterol that each crystallisation step obtains in irradiation step or the previous dissolving step, wherein, the fresh 7-dehydrogenation sterol with reclaiming is dissolved in the appropriate solvent, is preferably dissolved in the mixture of methyl alcohol and normal hexane, carry out irradiating step then.The solvent that distills out in the distilation steps also can be distinguished cycle applications in irradiating step or in the previous dissolving step.The mother liquor that keeps behind the final crystallisation step comprises reaction product (being provitamin D or derivatives thereof), undesirable by product and optional a spot of unreacted 7-dehydrogenation sterol (this 7-dehydrogenation sterol can not separate fully owing to have certain solvability in solvent).Can be by the amount of 7-dehydrogenation sterol in the following further minimizing solvent: reduce the temperature of final crystallisation step and/or carry out the 3rd and optional more crystallisation step.Yet can be determined by economic factors: it is also improper for the additional cost of cooling and/or other crystallisation step to reclaim a spot of extra 7-dehydrogenation sterol by these measures.Usually, 7-dehydrogenation sterol is because " loss " of its solvability in final mother liquor represented economic optimality for about 1 to 2% (according to provitamin of being produced).
In an embodiment of the invention, present method further comprises recovery provitamin D.The method that is suitable for reclaiming provitamin D is that those of ordinary skills are known, and it comprises normally used sepn process, for example chemical conversion by product, for example tachysterol; And industrial chromatography separates.If because can obtain provitamin D with highly selective by using present method, its purifying is easier so.
The invention still further relates to a kind of method for preparing vitamins D or its corresponding derivative by thermal rearrangement provitamin D or derivatives thereof.To the thermal transition of vitamins D is a kind ofly to carry out σ displacement 1 by C-19 to C-9, the conversion of 7-hydrogen, and it is suitable for after photochemical reaction the suitable moment in this method and carries out, and for example, thermal conversion can be carried out before or after 7-dehydrogenation sterol separates.During photodissociation, should avoid the thermal rearrangement of provitamin D,, thereby obtain further undesirable by product because vitamins D itself (or derivatives thereof) also can carry out phototransformation.
The method according to this invention comprises that also the corresponding derivative by irradiation 7-dehydrogenation sterol prepares the method for vitamin D-derivatives or provitamin D derivative.The derivative of 7-dehydrogenation sterol comprises all similar compounds of the 4-shown in (II) that has formula ring steroid class core, wherein, 9, the 10-key can carry out the photochemistry cracking, thereby obtains corresponding (Z)-triolefin.Can have extra substituting group arbitrarily on the above-mentioned similar compound, precondition is that substituting group can the stray light chemical conversion.Record all the elements in this application are applied to the derivative of vitamins D, the derivative of provitamin D and the derivative of 7-dehydrogenation sterol with being equal to.Usually, derivative includes but not limited to hydroxylated derivative and ester derivative.More specifically, the derivative of provitamin D is ester derivative or formula (I) derivative.
Wherein,
R
1Be
R
2Be H, hydroxyl or acyloxy;
R
3Be H, hydroxyl or acyloxy;
R
4Be H, CH
3, C
2H
5, hydroxyl or acyloxy;
Precondition is: R
2, R
3And R
4In at least one be hydroxyl or acyloxy (ester) base.
Term " ester derivative " or " ester " refer to that wherein the 3-OH matrix is by the derivative of esterifying organic acid, and it comprises the provitamin D ester of (a) formula (IV)
Wherein
R
1Be
R
2Be H; R
3Be H; R
4Be H, CH
3Or C
2H
5
R
5Be acyl group, preferably have 1-10 carbon atom, for example ethanoyl and benzoyl;
And the ester that comprises (b) provitamin D derivative, described ester is by with following formula (IV) expression, wherein
R
1Be
R
2Be H, hydroxyl or acyloxy;
R
3Be H, hydroxyl or acyloxy;
R
4Be H, CH
3, C
2H
5, hydroxyl or acyloxy;
R
5Be acyl group, preferably have 1-10 carbon atom, for example ethanoyl and benzoyl;
Precondition is: R
2, R
3And R
4In at least one be hydroxyl or acyloxy (ester) base.
The example of provitamin D/ vitamins D comprises 1 Alpha-hydroxy provitamin D
3/ 1 alpha-hydroxy vitamin D
3(1 Alpha-hydroxy cholecalciferol or α calcium glycol); 1 Alpha-hydroxy provitamin D
2/ 1 alpha-hydroxy vitamin D
2(1 Alpha-hydroxy angle wheat calciferol); 25-hydroxyl provitamin D
3/ 25-hydroxy-vitamin D
3(25-hydroxyl cholecalciferol or calcium glycol or calciferol or Hy-
); 25-hydroxyl provitamin D
2/ 25-hydroxy-vitamin D
2(25-hydroxyl ergocalciferol); 1 α, 25-dihydroxyl provitamin D
3/ 1 α, the 25-dihydroxyvitamin D
3(1 α, 25-dihydroxyl cholecalciferol, calcitriol); 1 α, 25-dihydroxyl provitamin D
2/ 1 α, the 25-dihydroxyvitamin D
2(1 α, 25-dihydroxyl ergocalciferol); 1 α, the 24-dihydroxyvitamin D
3/ 1 α, the 24-dihydroxyvitamin D
3(1 α, 24-dihydroxyl cholecalciferol or Tacalcitol tacalcitol); 24R, 25-dihydroxyl provitamin D
3/ 24R, the 25-dihydroxyvitamin D
3(24R, 25-dihydroxyl cholecalciferol or hydroxyl calcium glycol); Its ester and provitamin D
2/ vitamins D
2With provitamin D
3/ vitamins D
3The ester of itself.
Other that paid close attention to can vitamins D prepared in accordance with the present invention/provitamin D be the calcipotriol of formula V
And corresponding provitamin.Provitamin is made by shining its corresponding pro-vitamin.
In fact, concrete provitamin D derivative is made by the corresponding derivative of irradiation 7-dehydrogenation sterol: for example, and 25-hydroxyl provitamin D
325-hydroxy derivatives (the former D of 25-hydroxy vitamin by irradiation 7-DHC
3) and make.Similarly, provitamin D
3Ester by the irradiation 7-DHC the corresponding esters derivative make.
Now, in following non-limiting example, the present invention is further set forth.
Embodiment
The description of schema shown in Fig. 3,4,5:
Fig. 3:
1. solvent orange 2 A material solution jar
2. pro-vitamin B rayed reactor
3. pro-vitamin solution C UV light source
4. irradiated solution (circulation) D power supply
5. irradiated solution (finally)
Fig. 4:
1. solvent orange 2 A material solution jar
2. pro-vitamin B rayed reactor
3. pro-vitamin solution C UV light source
5. irradiated solution D power supply
The irradiated NaOH solution tank NaOH of E
Fig. 5:
5. irradiated solution F first crystallizer
6. the first pro-vitamin slurries G, first solid/liquid separation
7. the first washings H distills the unit
8. the vitaminogenic first wet cake I distillate collector
9. the first mother liquor J, second crystallizer
10. distillate K second solid/liquid separation
11. pro-vitamin solution
12. the second pro-vitamin slurries
13. second washings
14. the vitaminogenic second wet cake
15. second mother liquor
In this embodiment, use reaction unit shown in Figure 3, it adopts falling film reactor as rayed reactor (B).By being prepared as follows 7-DHC (pro-vitamin D
3) solution: 1000g normal hexane (1), 500g methyl alcohol (1), 2g BHA (tertiary butyl hydroxyanisol) and 80g 7-DHC (2) are added in the material NaOH solution tank NaOH (A).Under 35 ℃, stir above-mentioned substance, up to all 7-DHC dissolvings.Rayed reactor (B) comprises the medium pressure mercury lamp of 150W, and it adopts suitable power supply (D) power supply.Infeed 7-DHC solution (3) in the photoreactor (B) continuously and be circulated back in (4) material solution jar (A).Begin this experiment by connecting mercury lamp (C).Shone continuous 120 minutes.After closing mercury lamp (C), make solution circulated 15 minutes to carry out homogenize.By high performance liquid chromatography (HPLC) final irradiated solution (5) is analyzed.
The transformation efficiency of 7-DHC is 5.5%; Provitamin D
3Selectivity be 93.5%.
The reaction unit shown in Fig. 3 is also used in this experiment, carries out but be radiated in the falling film reactor (B) of the XeBr excimer lamp (C) that comprises 100W.Implement this embodiment according to embodiment 1 described process, difference is: use 0.5g BHA to substitute 2g BHA.
The transformation efficiency of 7-DHC is 7.8%; Provitamin D
3Selectivity be 96.0%.
In this embodiment, use reaction unit shown in Figure 4, it adopts falling film reactor as rayed reactor (B).By being prepared as follows 7-DHC (pro-vitamin D
3) solution: 4430g normal hexane (1), 2210g methyl alcohol (1), 0.5g BHA and 550g 7-DHC (2) are infeeded in the material solution jar (A).Under 35 ℃, stir above-mentioned substance, up to all 7-DHC dissolvings.Rayed reactor (B) comprises the medium pressure mercury lamp of 1500W, and it adopts suitable power supply (D) power supply.Connect mercury lamp (C).Start this experiment by beginning 7-DHC solution (3) infeeded in the photoreactor (B).Irradiated solution (5) is collected in the illuminated NaOH solution tank NaOH (E).When material solution jar (A) when emptying, stop irradiation.Therefore such single fraction irradiation can not obtain required transformation efficiency, repeats above-mentioned irradiation several times by shifting back irradiated solution (5) in the material solution jar (A) and in another process it being shone.After 7 times, irradiated solution (5) is analyzed with HPLC.
The transformation efficiency of 7-DHC is 8.4%; Provitamin D
3Selectivity be 86.7%.
This embodiment also uses the reaction unit shown in Fig. 4 and implements according to process described in the embodiment 3, but the consumption of raw material is as follows: 4420g normal hexane, 2110g methyl alcohol, 1g BHA and 860g 7-DHC.Stir above-mentioned raw materials down at 45 ℃, up to all 7-DHC dissolvings.
The transformation efficiency of 7-DHC is 5.8%; Provitamin D
3Selectivity be 89.0%.
This embodiment also uses reaction unit shown in Figure 4, carries out but be radiated in the falling film reactor (B) that comprises 3000W XeBr excimer lamp (C).By being prepared as follows the solution of 7-DHC: 6200g normal hexane (1), 3100g methyl alcohol (1), 1g BHA and 700g 7-DHC (2) are added in the material NaOH solution tank NaOH (A).Under 35 ℃, stir above-mentioned substance, up to all 7-DHC dissolvings.Connect XeBr excimer lamp (C).Start this experiment by beginning 7-DHC solution (3) infeeded in the photoreactor (B).Irradiated solution (5) is collected in the illuminated NaOH solution tank NaOH (E).When material solution jar (A) when emptying, stop irradiation.Therefore such single fraction irradiation can not obtain required transformation efficiency, repeats above-mentioned irradiation several times by shifting back irradiated solution (5) in the material solution jar (A) and in another process it being shone.After 3 times, irradiated solution (5) is analyzed with HPLC.
The transformation efficiency of 7-DHC is 5.5%; Provitamin D
3Selectivity be 96.2%.
After 6 times, analyze once more.
The transformation efficiency of 7-DHC is 10.7%; Provitamin D
3Selectivity be 93.5%.
In this embodiment, be used in combination reaction unit shown in Figure 4 and tripping device shown in Figure 5.By being prepared as follows the solution of 7-DHC: 8800g normal hexane (1), 4400g methyl alcohol (1), 1g BHA and 1000g 7-DHC (2) are added in the material NaOH solution tank NaOH (A).Under 35 ℃, stir above-mentioned substance, up to all 7-DHC dissolvings.Falling film reactor (B) comprises the XeBr excimer lamp (C) of 3000W, and it adopts suitable power supply (D) power supply.Connect XeBr excimer lamp (C).Start this experiment by beginning 7-DHC solution (3) infeeded in the photoreactor (B).When material solution jar (A) when emptying, stop irradiation.Make the single process obtain 5.6% required transformation efficiency by the flow velocity of regulating material solution.The provitamin D that the irradiation back obtains
3Selectivity be 93.6%.
3500g methyl alcohol is added in first crystallizer (F), this crystallizer is cooled to-20 ℃ then.Irradiated solution (5) is infeeded in first crystallizer (F) continuously.Under-20 ℃, the 7-DHC crystallization.The 7-DHC crystal is separated from mother liquor (9), with cold methanol (7) washing and dry (first output is 563g).
The mother liquor (9) that will comprise washings is transferred in the batch distillation unit (H), and by evaporation concentration, up to bottom residue 4585g.Bottoms (11) is transferred in second crystallizer (J), and be cooled to-20 ℃.Crystallization 7-DHC once more.7-DHC crystal (14) is separated from second mother liquor (15), with cold methanol (13) washing and dry (second batch output is 366g).Gained 7-DHC cycle applications to irradiating step, is about to it and introduces in the material solution jar (A), it is infeeded in the rayed reactor (B) as mentioned above then.
Claims (22)
1. one kind by the provitamin D of the 7-dehydrogenation sterol or derivatives thereof preparation formula (I) of formula (II) or the photochemical method of its corresponding derivative,
Wherein in formula (I) and formula (II),
R
1Be
Or
R
2Be H; R
3Be H; R
4Be H, CH
3Or C
2H
5,
Described method comprises: adopt the described 7-dehydrogenation of UV rayed sterol or derivatives thereof, up to the maximum conversion rate that is less than 12% 7-dehydrogenation sterol or derivatives thereof.
2. the method for claim 1, wherein shine described 7-dehydrogenation sterol or derivatives thereof, up to reaching 10% or the maximum conversion rate of littler 7-dehydrogenation sterol or derivatives thereof.
3. the method for claim 1, wherein shine described 7-dehydrogenation sterol or derivatives thereof, up to reaching 7% or the maximum conversion rate of littler 7-dehydrogenation sterol or derivatives thereof.
4. as any described method among the claim 1-3, wherein, be at least 80% for the selectivity of described provitamin D or derivatives thereof.
5. method as claimed in claim 4 wherein, is at least 85% for the selectivity of described provitamin D or derivatives thereof.
6. method as claimed in claim 5 wherein, is at least 90% for the selectivity of described provitamin D or derivatives thereof.
7. as any described method among the claim 1-6, wherein, the transformation efficiency of described 7-dehydrogenation sterol or derivatives thereof is at least 2%.
8. as any described method among the claim 1-7, comprise following additional step: (b) the unconverted 7-dehydrogenation of near small part sterol or derivatives thereof is separated from reaction mixture.
9. method as claimed in claim 8 comprises following additional step: (c) with isolated unconverted 7-dehydrogenation sterol or derivatives thereof cycle applications in irradiating step.
10. as any described method among the claim 1-9, wherein, irradiated described 7-dehydrogenation sterol or derivatives thereof is dissolved in the organic solvent.
11. method as claimed in claim 10 wherein, is dissolved in described 7-dehydrogenation sterol or derivatives thereof in normal hexane and the methanol mixture.
12., wherein, in step (b), separate described 7-dehydrogenation sterol or derivatives thereof and comprise at least one crystallisation step as claim 10 or 11 described methods.
13. method as claimed in claim 12 wherein, is separated described 7-dehydrogenation sterol or derivatives thereof and is comprised at least two crystallisation steps in step (b).
14. method as claimed in claim 13 wherein, is separated described 7-dehydrogenation sterol or derivatives thereof and is comprised in step (b):
(b1) make the described 7-dehydrogenation sterol or derivatives thereof crystallization of first quantity,
(b2) from reaction mixture, separate the described 7-dehydrogenation sterol or derivatives thereof of described first quantity by solid/liquid separation,
(b3) distill out partial solvent at least,
(b4) make the described 7-dehydrogenation sterol or derivatives thereof crystallization of second quantity,
(b5) from reaction mixture, separate the described 7-dehydrogenation sterol or derivatives thereof of described second quantity by solid/liquid separation.
15. further comprising, any described method in the claim as described above, described method reclaim described provitamin D or derivatives thereof.
16. as any described method among the claim 1-15, wherein, described 7-dehydrogenation sterol is ergosterol or 7-aphyllidine, described ergosterol is converted to provitamin D
2, described 7-aphyllidine is converted to provitamin D
3
17. method as claimed in claim 16, wherein, described 7-dehydrogenation sterol is to be converted to provitamin D
3The 7-aphyllidine.
18. as any described method among the claim 1-15, wherein, the derivative of provitamin D is ester or formula (I) derivative of provitamin D, wherein, and R
1, R
2, R
3And R
4Such as claim 1 definition, but difference is R
2, R
3And R
4In at least one be hydroxyl or acyloxy.
19. as any described method among the claim 1-15, wherein, the derivative of provitamin D is selected from by the provitamin of calcipotriol, 1 Alpha-hydroxy provitamin D
3, 1 Alpha-hydroxy provitamin D
225-hydroxyl provitamin D
3, 25-hydroxyl provitamin D
2, 1 α, 25-dihydroxyl provitamin D
3, 1 α, 25-dihydroxyl provitamin D
2, 1 α, 24-dihydroxyl provitamin D
3, 24R, 25-dihydroxyl provitamin D
3, acyloxy provitamin D
3, its ester and provitamin D
2And D
3The group formed of ester.
20. method as claimed in claim 19, wherein, the derivative of provitamin D is 25-hydroxyl provitamin D
3
21. any described method in the claim as described above, wherein, described being radiated in the falling film reactor carried out.
22. one kind by the vitamins D of the 7-dehydrogenation sterol or derivatives thereof preparation formula (III) of formula (II) or the method for its corresponding derivative:
Described method comprises:
According to provitamin D or its corresponding derivative of any described method preparation formula (I) in the claim 1 to 21,
Wherein in formula (I), formula (II) and formula (III),
R
1Be
Or
R
2Be H, R
3Be H, R
4Be H, CH
3Or C
2H
5And
By thermal rearrangement described provitamin D or derivatives thereof is changed into described vitamins D or derivatives thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP07008301.9 | 2007-04-24 | ||
| EP07008301 | 2007-04-24 |
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|---|---|
| CN101663269A true CN101663269A (en) | 2010-03-03 |
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ID=39816804
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|---|---|---|---|
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|---|---|
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| WO (1) | WO2008128782A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110713449A (en) * | 2019-11-12 | 2020-01-21 | 广西师范大学 | Efficient green production process of vitamin D3 |
| CN110724081A (en) * | 2019-11-12 | 2020-01-24 | 广西师范大学 | Efficient production process of vitamin D2 |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8263580B2 (en) | 1998-09-11 | 2012-09-11 | Stiefel Research Australia Pty Ltd | Vitamin formulation |
| CA2611147C (en) | 2005-06-01 | 2013-04-09 | Stiefel Research Australia Pty Ltd. | Topical emulsion formulation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3070985D1 (en) * | 1979-10-23 | 1985-09-19 | Teijin Ltd | Process for the preparation of active-type vitamin d3 compounds and of the cholesta-5,7-diene precursors, and products so obtained |
| IN188477B (en) * | 1998-06-23 | 2002-09-28 | Hoffmann La Roche |
-
2008
- 2008-04-24 CN CN200880013040A patent/CN101663269A/en active Pending
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110713449A (en) * | 2019-11-12 | 2020-01-21 | 广西师范大学 | Efficient green production process of vitamin D3 |
| CN110724081A (en) * | 2019-11-12 | 2020-01-24 | 广西师范大学 | Efficient production process of vitamin D2 |
| CN110724081B (en) * | 2019-11-12 | 2023-08-15 | 广西师范大学 | Efficient production process of vitamin D2 |
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| WO2008128782A3 (en) | 2008-12-11 |
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