CN104230981B - The preparation method of valproic acid phospholipid derivative - Google Patents
The preparation method of valproic acid phospholipid derivative Download PDFInfo
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Abstract
The invention belongs to organic compound preparation field, disclose the preparation method of valproic acid phospholipid derivative. The present invention makees solvent with oxolane, triethylamine is made acid binding agent, the third valeric chloride reacts at 10-50 DEG C with equimolar valproic acid, after filtration, distill to obtain valproic acid acid anhydride, in valproic acid anhydride solution, add lysophosphatidyl choline, under DMAP catalysis, at 60-85 DEG C, react 2-6 hour, add acetone precipitation product, then refine to obtain valproic acid phospholipid derivative by ethanol/acetone. The present invention uses valproic acid to react and prepare valproic acid acid anhydride with the third valeric chloride, does not have the impact of acetic anhydride, and easily purifying obtains highly purified valproic acid acid anhydride, and then can prepare highly purified valproic acid phospholipid derivative.
Description
Technical field
The invention belongs to organic compound preparation field, relate to the preparation method of valproic acid phospholipid derivative.
Background technology
Chinese patent application 01815173.6 discloses a kind of valproic acid phospholipid derivative and preparation method thereof, and this phosphatide spreads outBiological (DP-VPA) is mixture, and its two component is respectively 1-palmityl-sn-glyceryl-3-phosphocholine (C16-DP-VPA），1-stearoyl-sn-glyceryl-3-phosphocholine (C18-DP-VPA), structural formula is
Two component ratio C16-DP-VPA：C18-DP-VPA is 15 ± 5%:85 ± 5%, and this medicine is by D-Pharm company of IsraelExploitation, is used for the treatment of epilepsy, is at present clinical research.
This product is powerful anticonvulsant, and its essence is taking lysophosphatidyl choline as carrier, by active component VPA(the third pentaAcid) connect phosphatide in sn-2 position by ester bond, because phosphatide cpd essence is hydrophobic, therefore can permeate biomembrane and wallBuild, thereby impel medicine to cell or organ, for example, in the brain of its effect of needs, transport, valproic acid can pass through DP-VPA chemical combinationThing is in the cracking under phospholipase A2 or any other lipase or esterase effect and discharges at the position of phosphatide sn-2. The third pentaAcid moieties can further improve the therapeutic index of medicine in the adjustment release of lesions position, because potential side effect and toxicity subtractFew time, the effect of medicine is estimated to increase. Much lower compared with the dosage that this compound uses at present with VPA, and therapeutic doseReduction so that the side effect that has reduced again toxicology risk and followed, also reduced between itself and other drug simultaneously and do not wishedInteractional danger. This compound is expected to become the antiepileptic of a class excellence.
Chinese patent application 01815173.6 discloses the manufacture method of DP-VPA:
With C18-DP-VPA is example, and its synthetic route is:
The method is first under catalyst pyridine exists, and valproic acid adds hot preparation valproic acid acid anhydride in solution of acetic anhydride, soRear valproic acid acid anhydride and lysolecithin are at 90-100 DEG C, and under DMAP catalysis, DP-VPA, products obtained therefrom are prepared in reactionBy four recrystallizations of acetone/ethanol.
But there are some problems in the synthetic route of the method: the preparation of step 1 valproic acid acid anhydride is with valproic acid and excessiveAcetic anhydride, then by excessive acetic acid acid anhydride and by-product acetic acid, after catalyst pyridine steams and removes, distill repeatedly product obtains the third pentaAcid anhydrides. In this kind of preparation method's product, contain residual acetic anhydride, acetic acid valproic acid acid anhydride etc., can bring next step into and participate in reaction,Make to contain in product acetylate, and acetylate is through repeatedly being still difficult to eliminate after recrystallization, the method can not obtainHighly purified valproic acid acid anhydride, valproic acid acid anhydride is the key intermediate of preparation DP-VPA, valproic acid acid anhydride purity directly affects DP-VPAPurity. Preparing highly purified valproic acid acid anhydride is the key of synthetic DP-VPA, is necessary its synthesis technique to improve for this reason.In step 2, reaction temperature is at 90-100 DEG C, and the inventor uses this temperature products obtained therefrom color darker, and impurity content is higher, afterIn processing, product is not easy to separate out, and yield reduces, and recrystallization process wastes time and energy, causes productive rate to reduce.
Summary of the invention
The object of this invention is to provide a kind of cost lower, simple to operate, and product be easy to purifying valproic acid acid anhydride andValproic acid phospholipid derivative preparation method.
A preparation method for valproic acid phospholipid derivative, is characterized in that comprising the following steps:
A, use non-protonic solvent, organic base is made acid binding agent, and the third valeric chloride and equimolar valproic acid are anti-at 10-50 DEG CShould, after filtration, distill to obtain valproic acid acid anhydride;
In B, valproic acid anhydride solution, add lysophosphatidyl choline, under DMAP catalysis at 60-85 DEG CReaction 2-6 hour, adds acetone precipitation product, then refines to obtain valproic acid phospholipid derivative by ethanol/acetone.
The third described valeric chloride can be by valproic acid and excess chlorination sulfoxide back flow reaction, and steaming removes excess chlorination sulfoxide and obtainsArrive.
Wherein, reflux temperature is preferably 86～88 DEG C, and reflux time is 1～4h preferably, further preferably 1～2 hour.
In the preparation method of valproic acid phospholipid derivative of the present invention, the preferred benzene of non-protonic solvent described in A step, firstBenzene, any one or a few in carrene, ether or oxolane, further preferred oxolane; The preferred pyrrole of organic basePyridine or triethylamine, further preferred triethylamine; The preferred 10-40 DEG C of reaction temperature, further preferred 20-35 DEG C, reaction time 1-4h, preferably 1-2h.
In the preparation method of valproic acid phospholipid derivative of the present invention, DMAP and the hemolytic phosphatidyl courage of B stepThe mol ratio of alkali is 0.05-1:1, preferably 0.1-0.3:1; The preferred 62-80 DEG C of described reaction temperature, further preferably 70 ± 5DEG C, reaction time 3-4h.
With C18-DP-VPA is example, and the synthetic route of the inventive method is as follows:
The present invention compared with prior art has good effect: use valproic acid to react and prepare valproic acid with the third valeric chloride, there is not the impact of acetic anhydride in acid anhydride, easily purifying obtains highly purified valproic acid acid anhydride, and then can prepare highly purified valproic acidPhospholipid derivative. The thionyl chloride that this method is used, oxolane can recovery, and this reagent is compared to acetic anhydride,Pyridine, price is more cheap, and method of the present invention is more economical, environmental protection. The reaction temperature of valproic acid acid anhydride and lysophosphatidyl choline is fallenLow to 60 ?85 DEG C, reduced the content of accessory substance, improved product yield and purity, the product colour of avoiding high temperature to cause is darkAnd impurity content is high, the shortcoming that end-product yield is low.
Detailed description of the invention
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention to described realityExecute among routine scope.
Embodiment 1C18-DP-VPA's is synthetic
(1) valproic acid acid anhydride preparation
A step: add 1.4L thionyl chloride in 2L reaction bulb, drip 700g valproic acid, dropwise, be warming up to 86 DEG C of backflows2h, revolves to steam and removes excessive thionyl chloride, and gained residue is for subsequent use.
B step: separately have 5L reaction bulb, add 2L oxolane, 491g triethylamine, slowly adds 700g valproic acid under stirring,Then drip above-mentioned residue, dropwise, 10 DEG C of stirring reaction 4h, suction filtration, filter cake washs with oxolane, and filtrate is revolved to steam and is removedRemove oxolane, residue vacuum distillation, collects 125-127 DEG C/54Pa cut and obtains valproic acid acid anhydride 1089g, valproic acid acid anhydride yield82.8%, purity is 99.4%.
(2) C18-DP-VPA preparation
In 5L reaction bulb, add 190gC18-lysophosphatidyl choline, 9.5g4-dimethylamino naphthyridine (DMAP) and 260g thirdValeric anhydride is warming up to 60 DEG C of reaction 4h, and solution clarification, is cooled to 20 DEG C, drips 19 times of volume acetone, drips and finishes, and is cooled to 0 DEG C and stirsMix 2h, suction filtration, 50 DEG C of vacuum drying, gained crude product adds 20 DEG C of stirring and dissolving of 1.1 times of volume absolute ethyl alcohols in 5L reaction bulb,Drip the acetone of 12.5 times of volumes, drip and finish, be cooled to 0 DEG C and stir 2h, suction filtration, 50 DEG C of vacuum drying, obtain products C18-DP-VPA is common174g, yield 73.8%, purity is 99.2%.
Comparative example 1:
(1) valproic acid acid anhydride preparation
In 5L reaction bulb, add 700g valproic acid, 2480g acetic anhydride, 384g pyridine, is warming up to 90 DEG C of reaction 4h, and vacuum is steamedHeat up in a steamer, remove front-end volatiles, collect 125-127 DEG C/54Pa left and right and stablize cut, obtain valproic acid acid anhydride 328g product distill repeatedly 2-3 time,Yield 50%. (purity is 91%, GC)
(2) C18-DP-VPA preparation
In 5L reaction bulb, add 190gC18-lysophosphatidyl choline, 5.5gDMAP and 260g valproic acid acid anhydride are warming up to 90 DEG CReaction 3h, solution clarification, is cooled to 20 DEG C, drips 19 times of volume acetone, drips and finishes, and be cooled to 0 DEG C and stir 2h, suction filtration, 50 DEG C are trueEmpty dry, gained crude product adds 20 DEG C of stirring and dissolving of 1.1 times of volume absolute ethyl alcohols in 5L reaction bulb, 12.5 times of volumes of droppingAcetone, drips and finishes, and be cooled to 0 DEG C and stir 2h, suction filtration, 50 DEG C of vacuum drying, above-mentioned subtractive process repeats 2-3 time, obtains productC18-DP-VPA101g(purity is 96.4%, HPLC), yield 43%.
Embodiment 2C18-DP-VPA's is synthetic
(1) valproic acid acid anhydride preparation
A step: add 1.4L carrene in 2L reaction bulb, drip 700g valproic acid, dropwise, be warming up to 86 DEG C of backflows2h, revolves to steam and removes excessive thionyl chloride, and gained residue is for subsequent use.
B step: separately have 5L reaction bulb, add 2L oxolane, 500g pyridine, slowly adds 700g valproic acid under stirring, soThe above-mentioned residue of rear dropping, dropwises, and 35 DEG C are stirred 1.5h, suction filtration, and filter cake washs with oxolane, and filtrate is revolved to steam and is removed fourHydrogen furans, residue vacuum distillation, collects 125-127 DEG C/54Pa cut and obtains valproic acid acid anhydride 1059g, valproic acid acid anhydride yield80.6%, purity is 99.3%.
(2) C18-DP-VPA preparation
In 5L reaction bulb, add 190gC18-lysophosphatidyl choline, 4.5gDMAP and 260g valproic acid acid anhydride are warming up to 70 DEG CReaction 4h, solution clarification, is cooled to 20 DEG C, drips 19 times of volume acetone, drips and finishes, and be cooled to 0 DEG C and stir 2h, suction filtration, 50 DEG C are trueEmpty dry, gained crude product adds 20 DEG C of stirring and dissolving of 1.1 times of volume absolute ethyl alcohols in 5L reaction bulb, 12.5 times of volumes of droppingAcetone, drips and finishes, and be cooled to 0 DEG C and stir 2h, suction filtration, 50 DEG C of vacuum drying, obtain products C18-DP-VPA is 165g altogether, and yield 70% is pureDegree is 99.1%.
Embodiment 3C18-DP-VPA's is synthetic
(1) valproic acid acid anhydride preparation
A step: in 2L reaction bulb, add 1.4L ethane, drip 700g valproic acid, dropwise, be warming up to 88 DEG C of backflow 2h,Revolve to steam and remove excessive thionyl chloride, gained residue is for subsequent use.
B step: separately have 5L reaction bulb, add 2L oxolane, 491g triethylamine, slowly adds 700g valproic acid under stirring,Then drip above-mentioned residue, dropwise, 25 DEG C are stirred 1h, suction filtration, and filter cake washs with oxolane, and filtrate is revolved to steam and is removed fourHydrogen furans, residue vacuum distillation, 125-127 DEG C/54Pa of collection stablizes cut in left and right and obtains valproic acid acid anhydride 1070g, valproic acid acid anhydrideYield 81.5%, purity is 99.1%.
(2) C18-DP-VPA preparation
In 5L reaction bulb, add 190gC18-lysophosphatidyl choline, 13.3gDMAP and 260g valproic acid acid anhydride are warming up to 80DEG C reaction 3h, solution clarification, is cooled to 20 DEG C, drips 19 times of volume acetone, drips and finishes, and is cooled to 0 DEG C of stirring 2h, suction filtration, 50 DEG CVacuum drying, gained crude product adds 20 DEG C of stirring and dissolving of 1.1 times of volume absolute ethyl alcohols in 5L reaction bulb, drips 12.5 times of volumesAcetone, drip finish, be cooled to 0 DEG C stir 2h, suction filtration, 50 DEG C of vacuum drying, obtain products C18-DP-VPA180g, yield 76.4%,Purity is 99.0%.
Embodiment 4C18-DP-VPA's is synthetic
(1) valproic acid acid anhydride preparation
A step: add 1.4L thionyl chloride in 2L reaction bulb, drip 700g valproic acid, dropwise, be warming up to 86 DEG C of backflows2h, revolves to steam and removes excessive thionyl chloride, and gained residue is for subsequent use.
B step: separately have 5L reaction bulb, add 2L oxolane, 491g triethylamine, slowly adds 700g valproic acid under stirring,Then drip above-mentioned residue, dropwise, 50 DEG C are stirred 2h, suction filtration, and filter cake washs with oxolane, and filtrate is revolved to steam and is removed fourHydrogen furans, residue vacuum distillation, 125-127 DEG C/54Pa of collection stablizes cut in left and right and obtains valproic acid acid anhydride 1050g, valproic acid acid anhydrideYield 80%, purity is 99.3%.
(2) C18-DP-VPA preparation
In 5L reaction bulb, add 190gC18-lysophosphatidyl choline, 11.2gDMAP and 260g valproic acid acid anhydride are warming up to 85DEG C reaction 3h, solution clarification, is cooled to 20 DEG C, drips 19 times of volume acetone, drips and finishes, and is cooled to 0 DEG C of stirring 2h, suction filtration, 50 DEG CVacuum drying, gained crude product adds 20 DEG C of stirring and dissolving of 1.1 times of volume absolute ethyl alcohols in 5L reaction bulb, drips 12.5 times of volumesAcetone, drip finish, be cooled to 0 DEG C stir 2h, suction filtration, 50 DEG C of vacuum drying, obtain products C18-DP-VPA170g, yield 72% is pureDegree is 99.1%.
Embodiment 5C18-DP-VPA's is synthetic
(1) valproic acid acid anhydride preparation
A step: in 2L reaction bulb, add 1.5L toluene, drip 700g valproic acid, dropwise, be warming up to 86 DEG C of backflow 2h,Revolve to steam and remove excessive thionyl chloride, gained residue is for subsequent use.
B step: separately have 5L reaction bulb, add 2L oxolane, 491g pyridine, slowly adds 700g valproic acid under stirring, soThe above-mentioned residue of rear dropping, dropwises, and 50 DEG C are stirred 2h, suction filtration, and filter cake washs with oxolane, and filtrate is revolved to steam and is removed tetrahydrochyseneFurans, residue vacuum distillation, 125-127 DEG C/54Pa of collection stablizes cut in left and right and obtains valproic acid acid anhydride 1072g, and valproic acid acid anhydride is receivedRate 81.6%, purity is 99.2%.
(2) C18-DP-VPA preparation
In 5L reaction bulb, add 190gC18-lysophosphatidyl choline, 5.5gDMAP and 260g valproic acid acid anhydride are warming up to 62 DEG CReaction 3h, solution clarification, is cooled to 20 DEG C, drips 19 times of volume acetone, drips and finishes, and be cooled to 0 DEG C and stir 2h, suction filtration, 50 DEG C are trueEmpty dry, gained crude product adds 20 DEG C of stirring and dissolving of 1.1 times of volume absolute ethyl alcohols in 5L reaction bulb, 12.5 times of volumes of droppingAcetone, drips and finishes, and be cooled to 0 DEG C and stir 2h, suction filtration, 50 DEG C of vacuum drying, obtain products C18-DP-VPA175g, yield 74.2% is pureDegree is 99.2%.
Embodiment 6C18-DP-VPA's is synthetic
(1) valproic acid acid anhydride preparation
A step: add 1.4L thionyl chloride in 2L reaction bulb, drip 700g valproic acid, dropwise, be warming up to 86 DEG C of backflows2h, revolves to steam and removes excessive thionyl chloride, and gained residue is for subsequent use.
B step: separately have 5L reaction bulb, add 2L oxolane, 491g triethylamine, slowly adds 700g valproic acid under stirring,Then drip above-mentioned residue, dropwise, 50 DEG C are stirred 2h, suction filtration, and filter cake washs with oxolane, and filtrate is revolved to steam and is removed fourHydrogen furans, residue vacuum distillation, 125-127 DEG C/54Pa of collection stablizes cut in left and right and obtains valproic acid acid anhydride 1068g, valproic acid acid anhydrideYield 81.4%, purity is 99.5%.
(2) C18-DP-VPA preparation
In 5L reaction bulb, add 190gC18-lysophosphatidyl choline, 7.5gDMAP and 260g valproic acid acid anhydride are warming up to 75 DEG CReaction 3h, solution clarification, is cooled to 20 DEG C, drips 19 times of volume acetone, drips and finishes, and be cooled to 0 DEG C and stir 2h, suction filtration, 50 DEG C are trueEmpty dry, gained crude product adds 20 DEG C of stirring and dissolving of 1.1 times of volume absolute ethyl alcohols in 5L reaction bulb, 12.5 times of volumes of droppingAcetone, drips and finishes, and be cooled to 0 DEG C and stir 2h, suction filtration, 50 DEG C of vacuum drying, obtain products C18-DP-VPA168g, yield 71.3% is pureDegree is 99.4%.
Embodiment 7C18-DP-VPA's is synthetic
(1) valproic acid acid anhydride preparation
A step: add 1.4L thionyl chloride in 2L reaction bulb, drip 700g valproic acid, dropwise, be warming up to 86 DEG C of backflows2h, revolves to steam and removes excessive thionyl chloride, and gained residue is for subsequent use.
B step: separately have 5L reaction bulb, add 2L oxolane, 491g triethylamine, slowly adds 700g valproic acid under stirring,Then drip above-mentioned residue, dropwise, 50 DEG C are stirred 3h, suction filtration, and filter cake washs with oxolane, and filtrate is revolved to steam and is removed fourHydrogen furans, residue vacuum distillation, 125-127 DEG C/54Pa of collection stablizes cut in left and right and obtains valproic acid acid anhydride 1080g, valproic acid acid anhydrideYield 82.3%, purity is 99.4%.
(2) C18-DP-VPA preparation
In 5L reaction bulb, add 190gC18-lysophosphatidyl choline, 44gDMAP and 260g valproic acid acid anhydride are warming up to 65 DEG CReaction 3h, solution clarification, is cooled to 20 DEG C, drips 19 times of volume acetone, drips and finishes, and be cooled to 0 DEG C and stir 2h, suction filtration, 50 DEG C are trueEmpty dry, gained crude product adds 20 DEG C of stirring and dissolving of 1.1 times of volume absolute ethyl alcohols in 5L reaction bulb, 12.5 times of volumes of droppingAcetone, drips and finishes, and be cooled to 0 DEG C and stir 2h, suction filtration, 50 DEG C of vacuum drying, obtain products C18-DP-VPA160g, yield 67.9% is pureDegree is 99.2%.
Embodiment 8
(1) valproic acid acid anhydride preparation
A step: add 1.4L thionyl chloride in 2L reaction bulb, drip 700g valproic acid, dropwise, be warming up to 88 DEG C of backflows2h, revolves to steam and removes excessive thionyl chloride, and gained residue is for subsequent use.
B step: separately have 5L reaction bulb, add 2L oxolane, 491g triethylamine, slowly adds 700g valproic acid under stirring,Then drip above-mentioned residue, dropwise, 25 DEG C are stirred 1h, suction filtration, and filter cake washs with oxolane, and filtrate is revolved to steam and is removed fourHydrogen furans, residue vacuum distillation, 125-127 DEG C/54Pa of collection stablizes cut in left and right and obtains C18-DP-VPA1070g, valproic acid acid anhydrideYield 81.5%, purity is 99.3%.
(2) C16-DP-VPA preparation
In 5L reaction bulb, add 190gC16-lysophosphatidyl choline, 2.2gDMAP and 260g valproic acid acid anhydride are warming up to 80 DEG CReaction 3h, solution clarification, is cooled to 20 DEG C, drips 19 times of volume acetone, drips and finishes, and be cooled to 0 DEG C and stir 2h, suction filtration, 50 DEG C are trueEmpty dry, gained crude product adds 20 DEG C of stirring and dissolving of 1.1 times of volume absolute ethyl alcohols in 5L reaction bulb, 12.5 times of volumes of droppingAcetone, drips and finishes, and be cooled to 0 DEG C and stir 2h, suction filtration, 50 DEG C of vacuum drying, obtain products C16-DP-VPA180g, yield 76.4% is pureDegree is 99.2%.
Embodiment 9C16/C18The preparation of-DP-VPA mixture
C16/C18The preparation of-DP-VPA mixture is made according to the identical DP-VPA preparation procedure in embodiment 1, and difference existsObtained by soybean and reach capacity by hydrogenation in this lysolecithin.
Claims (12)
1. a preparation method for valproic acid phospholipid derivative, is characterized in that comprising the following steps:
A, use non-protonic solvent, organic base is made acid binding agent, and the third valeric chloride reacts at 10-50 DEG C with equimolar valproic acid,After filtration, distill to obtain valproic acid acid anhydride;
In B, valproic acid anhydride solution, add lysophosphatidyl choline, reaction at 60-85 DEG C under DMAP catalysis2-6 hour, adds acetone precipitation product, then refines to obtain valproic acid phospholipid derivative by ethanol/acetone.
2. method according to claim 1, is characterized in that the third described valeric chloride is by valproic acid and excess chlorination AsiaSulfone back flow reaction, steaming removes excess chlorination sulfoxide and obtains.
3. method according to claim 2, is characterized in that described reflux temperature is 86 ~ 88 DEG C, reflux timeBe 1 ~ 4h.
4. method according to claim 3, is characterized in that described reflux temperature is 86 ~ 88 DEG C, reflux timeIt is 1 ~ 2 hour.
5. method according to claim 1, is characterized in that the non-protonic solvent described in described A step is selected from dichloromethaneAny one in alkane, ethane, ether, toluene or oxolane; Organic base is pyridine or triethylamine; Reaction temperature is 10 ~ 40DEG C, the reaction time is 1 ~ 4h.
6. method according to claim 5, is characterized in that described non-protonic solvent is oxolane; Organic base isTriethylamine.
7. method according to claim 5, is characterized in that in described A step that the reaction time is 1 ~ 2h.
8. method according to claim 5, is characterized in that in described A step, reaction temperature is 20 ~ 35 DEG C.
9. method according to claim 1, is characterized in that DMAP and hemolytic phosphatidyl courage that described B walksThe mol ratio of alkali is 0.05 ~ 1:1.
10. method according to claim 9, is characterized in that DMAP and hemolytic phosphatidyl that described B walksThe mol ratio of choline is 0.1 ~ 0.3:1.
11. methods according to claim 1, is characterized in that the reaction temperature of described B step is 62 ~ 80 DEG C, the reaction timeBe 3 ~ 4h.
12. methods according to claim 11, is characterized in that the reaction temperature of described B step is 70 ± 5 DEG C.
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| DE102004024909A1 (en) * | 2004-05-19 | 2005-12-15 | Heinz Prof. Dr. Langhals | New perylene based dye compounds useful e.g. as fluorescence dyes or pigments in: glue colors, watercolors, colors for inkjet printer, printing inks, inks or lacquers; as vat dyes for e.g. paper, jute or hemp and for fluorescence cooling |
| CN1774252A (en) * | 2000-07-12 | 2006-05-17 | 迪-药品有限公司 | Phospholipid derivatives of valproic acid and mixtures thereof |
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| CN1774252A (en) * | 2000-07-12 | 2006-05-17 | 迪-药品有限公司 | Phospholipid derivatives of valproic acid and mixtures thereof |
| DE102004024909A1 (en) * | 2004-05-19 | 2005-12-15 | Heinz Prof. Dr. Langhals | New perylene based dye compounds useful e.g. as fluorescence dyes or pigments in: glue colors, watercolors, colors for inkjet printer, printing inks, inks or lacquers; as vat dyes for e.g. paper, jute or hemp and for fluorescence cooling |
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