CN103772433A - Synthetic method of chemiluminescence reagent AMPPD for immunization analysis - Google Patents
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Abstract
The invention discloses a synthetic method of chemiluminescence reagent AMPPD for immunization analysis. 3-methoxy benzaldehyde with cheap price is used as raw material, and six reactions including acetalation, substitution, condensation, demethylation, phosphorylation and photooxidation are carried out, and AMPPD is synthesized efficiently with overall yield of 36%. 3-methoxy benzaldehyde with cheap price is used as raw material, which substantially reduces the cost; the phosphorylation method in the synthesis route is improved, and the yield of the phosphorylation reaction is increased; strict waterless and oxygen-free operation does not related in the synthesis route, and the reaction yield in the synthesis process is high, so the method is suitable for industrial production, and overcomes the disadvantage that the synthesis route at the present market is not easy to be used in large scale production.
Description
Technical field
The present invention relates to the preparation method of chemical illuminating reagent, especially the synthetic method of 4-methoxyl group-4-(3-phosphoric acid acyl phenyl) spiral shell [1,2-dioxane-3,2 '-diamantane] disodium salt (being called for short AMPPD).
Background technology
AMPPD is the chemical luminous substrate of alkaline phosphatase, and in suitable buffered soln, along with the catalytic hydrolysis effect of enzyme, AMPPD resolves into AMP-D, and the latter sends the optical signal that intensity is very high, and its luminous speed depends on the concentration of alkali phosphorus enzyme.In the time that alkali phosphorus enzyme is coupled to the probe of hybridization, the amount of hybrid molecule just can be detected by this system.Be widely used as at present the luminous substrate of chemiluminescence immune assay, there is very high detection sensitivity, be applicable to detect the material of various molecular weight, stable luminous substrate, detected result is stable, reproducible, detect linear wide ranges, do not need special luminous substrate-antigen/antibody connector, convenience, easily use, can apply the advantages such as multiple analytical model (sandwich, competition, antibody test etc.), medically promoting the use of.But because its price is higher, limit its large-scale development and used.The major cause that price is high is comparatively difficulty of this material preparation, synthesis technique complexity.
Its preparation at present mainly contains four routes.
The first synthetic method is one piece of patent (patent No. EP0518387) in Europe, be that raw material is prepared the firm alkane of key intermediate substituted-phenyl methoxyl group methene fund by 2-diamantane ketone and 3-hydroxy-benzoic acid formic acid at metallic compound, then prepare AMPPD(by conventional photoxidation and see formula three), this reaction method flow process is short, efficiency is high, to complete reaction with the catalyst system of Lithium Aluminium Hydride/anhydrous titanous chloride composition but prepare key intermediate crucial catalyzer used, but anhydrous titanous chloride performance is active, belong to spontaneously combustible, meet air and water burning or blast, tool strong and stimulating, to mucous membrane, the upper respiratory tract, eye and skin have strong impulse.After suction, can be because of larynx and bronchial spasm, inflammation, oedema, chemical pneumonitis or pulmonary edema and lethal.After contact, cause burning sensation, cough, pant, laryngitis, breathe hard, have a headache, feel sick, vomiting etc., have not yet to see large-scale production, also there is no the mass-producing supply of commodities of Using such method.
The second synthetic method is one piece of Chinese patent (patent No. 102030779), it improves European patent, in patent, replace this catalyst system of Lithium Aluminium Hydride/anhydrous titanous chloride, used any catalyst system in anhydrous titanium tetrachloride/Lithium Aluminium Hydride, anhydrous titanium tetrachloride/zinc, these the three kinds of combinations of anhydrous titanium tetrachloride/tin instead.The method efficiently solves the shortcoming of the anhydrous titanous chloride that uses high risk, but still will under the condition of absolute anhydrous and oxygen-free, complete in actual building-up process.Therefore, this method is only suitable for a small amount of in laboratory and synthesizes, and is not suitable for industrial production, thereby has limited a large amount of productions of AMPPD.
TiCl
4/ LAH or TiCl
4/ Zn or TiCl
4/ Sn
The third method is to form two keys by the prussiate of diamantane and the Grignard reagent of replacement to obtain the firm alkane of key intermediate substituted-phenyl methoxyl group methene fund, then obtain AMPPD(by conventional photooxidation reaction and see formula two) (United States Patent (USP), the patent No. 4956477; United States Patent (USP), the patent No. 6417380; United States Patent (USP), the patent No. 6124478; European patent, the patent No. 0582317 etc.), the method flow process is oversize, use hypertoxic prussiate, has used Grignard reagent in process simultaneously, makes complicated operation, produces danger, therefore also can not realize the large-scale production of AMPPD.
The 4th kind of synthetic method is one piece of Chinese patent (patent No. 200510021054), in patent, adopting 2-diamantane ketone and 3-dimethyl tertiary butyl siloxy-1-(1 '-p diethylaminobenzoic acid ester group)-benzyl methyl ether is raw material, react by Wittig, obtain [(3-dimethyl tertiary butyl siloxy phenyl) methoxyl group methene alkane] diamantane, obtain AMPPD by photoxidation.The method cost of material is high, and synthesis step is long, and in phosphorylation process, uses the method for phosphorus oxychloride Direct Phosphorylation to be difficult to obtain the disodium salt of solid, extremely affects the recrystallization purifying of final product.
Therefore,, although there has been several pieces of synthetic methods about AMPPD report, do not have at present a kind of suitable method and realizes the industrial production of AMPPD.
Summary of the invention
The object of the invention is to the deficiency for existing AMPPD synthetic method, the new synthetic method of a kind of AMPPD is provided.
In order to achieve the above object, the present invention has adopted following technical scheme:
For a synthetic method of the chemical illuminating reagent AMPPD of immunoassay, the method synthetic route is as follows:
Wherein, in compound 1, R group is methyl or ethyl;
Concrete synthesis step is as follows:
Step a, condensation reaction: in ether solvent, under the effect of alkali, there is condensation reaction with 2-diamantane ketone and obtain compound 2 in compound 1, alkali is any in LDA, LHMDS, n-Butyl Lithium, tert-butyl lithium, potassium tert.-butoxide, sodium tert-butoxide and sodium hydride, the temperature that adds alkali is-80 ℃ ~ 10 ℃, ether solvent is a kind in methyl tertiary butyl ether, isopropyl ether, ether, tetrahydrofuran (THF) and Isosorbide-5-Nitrae-dioxane;
Step b, demethylating reaction: compound 2 reacts and obtains compound 3 with sulfur alcohol sodium under heating condition, sulfur alcohol sodium is with the amount of substance of compound 2 than being 3:1 ~ 0.9:1, and temperature of reaction is 50 ℃ ~ 190 ℃, and reaction solvent is any in DMF, DMSO and THF;
Step c, phosphorylation reaction: compound 3 and 3-hydroxypropionitrile phosphorylation under the effect of acid binding agent, phosphorylation process solvent is any in acetonitrile, tetrahydrofuran (THF), acetonitrile, methyl tertiary butyl ether and methylene dichloride, acid binding agent is any in pyridine, triethylamine, diisopropyl ethyl amine and DMAP, and the mineral alkali when hydrolysis of di(2-ethylhexyl)phosphate propionitrile ester is any in NaOH, sodium carbonate, sodium bicarbonate and sodium hydride;
Steps d, photooxidation reaction: compound 4, under the effect of photooxidation catalyst, is reacted and obtained final product AMPPD by rayed; Light source is high-pressure mercury lamp or the high voltage mercury lamp of power at 200W ~ 2000W, and photooxidation catalyst is any in Methylene blue, methylene blue, tropeolin-D and methyl red, and compound 4 is 100:10 ~ 100:0.001 with the weight feed ratio of catalyzer.
Preferably, compound 1 is synthetic by following method:
R=methyl, ethyl
First there is acetalation: m-methoxybenzaldehyde 5 does under solution, acid catalyzed effect and reacts and obtain compound 6 with methyl alcohol with trimethyl orthoformate, the volume ratio of methyl alcohol and trimethyl orthoformate is 0.1:1 ~ 1:0.1, acid is any in the vitriol oil, concentrated hydrochloric acid, phosphoric acid, acetic acid, p-methyl benzenesulfonic acid monohydrate, ammonium chloride, tartrate and citric acid, m-methoxybenzaldehyde 5 is with sour amount of substance than being 1:0.01 ~ 1:0.5, and this step temperature of reaction is 20 ℃ ~ 95 ℃;
There is again substitution reaction: compound 6 obtains compound 1 with phosphorous acid ester under the katalysis of Lewis acid, and phosphorous acid ester is triethyl-phosphite or trimethyl phosphite.Lewis acid is any in Zinc Chloride Anhydrous, boron trifluoride diethyl etherate, boron trichloride, aluminum trichloride (anhydrous) and FERRIC CHLORIDE ANHYDROUS, and the temperature that adds Lewis acid is-30 ℃ ~ 40 ℃.
Preferably, in the acetalation step of synthetic compound 1, in the time that reaction conditions meets following condition, this reaction can obtain more excellent result: the volume ratio of methyl alcohol and trimethyl orthoformate is 0.9:1 ~ 1.26:1, acid is any in the vitriol oil, acetic acid and p-methyl benzenesulfonic acid monohydrate, m-methoxybenzaldehyde is with sour amount of substance than being 1:0.1, and temperature of reaction is 65 ℃ ~ 80 ℃.In the substitution reaction step of synthetic compound 1, in the time that reaction conditions meets following condition, this reaction can obtain more excellent result: Lewis acid for Zinc Chloride Anhydrous or boron trifluoride diethyl etherate, and it is-20 ℃ ~-5 ℃ that Lewis acid adds fashionable temperature.
Especially, when in the acetalation step of synthetic compound 1, acid is acetic acid, and the volume ratio of methyl alcohol and trimethyl orthoformate is 1:1, and now this reaction can obtain optimum result; In the substitution reaction step of synthetic compound 1, phosphorous acid ester is triethyl-phosphite, and Lewis acid is Zinc Chloride Anhydrous, and now this reaction can obtain optimum result.
Preferably, in the time that step a reaction conditions meets following condition, this step reaction can obtain more excellent result: alkali is LDA or LHMDS, and the temperature that adds alkali is-75 ℃ ~-50 ℃, and solvent is methyl tertiary butyl ether or tetrahydrofuran (THF).
Preferably, in the time that step b reaction conditions meets following condition, this reaction can obtain more excellent result: sulfur alcohol sodium is with the amount of substance of reaction raw materials than being 1.05:1 ~ 2:1, and temperature of reaction is 100 ℃ ~ 140 ℃.
Preferably, in the time that step c reaction conditions meets following condition, this reaction can obtain more excellent result: phosphorylation process solvent is tetrahydrofuran (THF), and acid binding agent is pyridine or triethylamine.
Preferably, in the time that steps d reaction conditions meets following condition, this reaction can obtain more excellent result: the high-pressure mercury lamp that light source is 800W, and photooxidation catalyst is methylene blue, the weight feed ratio of raw material and catalyzer is 100:5 ~ 100:0.1.
Especially,, when alkali in step a is LHMDS, reaction solvent is methyl tertiary butyl ether; In step b, sulfur alcohol sodium is with the amount of substance of compound 2 than being 1.2:1, and reaction solvent is DMF; In step c, the solvent of phosphorylation process is that tetrahydrofuran (THF), alkali are pyridine, and the mineral alkali when hydrolysis of di(2-ethylhexyl)phosphate propionitrile ester is NaOH; In steps d, compound 4 is 197:1 with the weight feed ratio of methylene blue, and now, this synthetic method can obtain optimal result.
The present invention, from low-cost m-methoxybenzaldehyde, greatly reduces cost; In synthetic route, improve the method for phosphorylation, improved the productive rate of phosphorylation reaction; In synthetic route, do not relate to strict anhydrous and oxygen-free operation, in building-up process, reaction yield is all very high, and synthetic total recovery is 36%, and the present invention is suitable for industrial production, has solved existing market synthetic route and has been difficult for amplifying the shortcoming of producing.
Accompanying drawing explanation
Fig. 1 is the nuclear magnetic spectrogram of AMPPD;
Fig. 2 is the infrared spectrogram of AMPPD.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is done further to explanation clearly and completely.
Embodiment
The synthetic of 3-methoxyl group-1-in embodiment (1 '-p diethylaminobenzoic acid ester group) benzyl methyl ether 1 can adopt following two-step reaction:
First there is acetalation: by 5136 grams of m-methoxybenzaldehydes (1mol), be dissolved in 200mL methyl alcohol, add successively at normal temperatures (6 grams of trimethyl orthoformate 200mL and acetic acid, 0.1mol) (in other embodiments, the volume ratio of methyl alcohol and trimethyl orthoformate is 0.1:1 ~ 1:0.1, when time in the volume ratio of methyl alcohol and the trimethyl orthoformate scope at 0.9:1 ~ 1.26:1 reacts and can reach a preferably effect, acid such as replaces with at the vitriol oil of amount of substance, concentrated hydrochloric acid, phosphoric acid, p-methyl benzenesulfonic acid monohydrate, ammonium chloride, tartrate, any in citric acid, m-methoxybenzaldehyde is 1:0.01 ~ 1:0.5 with sour amount of substance ratio).Heating reflux reaction 10 hours (temperature of reaction is controlled at 20 ℃ ~ 95 ℃ in other embodiments) at 65 ℃ ~ 80 ℃, decompression is revolved after desolventizing, adds ethyl acetate, washes twice with saturated sodium bicarbonate solution, and organic layer is washed till neutrality with saturated nacl aqueous solution.Dry filter, concentrated, obtains 1-(dimethoxy-methyl)-6169 grams of 3-anisoles through underpressure distillation, and productive rate is 93%,
1h NMR(300MHz, CDCl
3) δ 3.22(d, 6H), 3.90 (s, 3H), 5.60 (m, 1H), 7.09-7.20 (m, 4H).
Substitution reaction: 1-(dimethoxy-methyl)-6182 grams of 3-anisoles (1mol) occur to be again dissolved in 300mL methylene dichloride, add triethyl phosphate 199 grams (1.2mol) (in other embodiments, triethyl phosphate such as replaces with at the trimethyl phosphite 99 of amount of substance).At-20 ℃ ~-5 ℃, add (204 grams of Zinc Chloride Anhydrouss, tetrahydrofuran solution (150mL) 1.5mol) rises to room temperature reaction 10 hours (in other embodiments naturally, Zinc Chloride Anhydrous such as replaces with at any in boron trifluoride diethyl etherate, boron trichloride, aluminum trichloride (anhydrous) and the FERRIC CHLORIDE ANHYDROUS of amount of substance, adds the temperature of Zinc Chloride Anhydrous to be controlled at-30 ℃ ~ 40 ℃).Use saturated NaHCO
3after washing, anhydrous sodium sulfate drying, is spin-dried for.Underpressure distillation, obtains 1239 grams of 3-methoxyl group-1-(1 '-p diethylaminobenzoic acid ester group) benzyl methyl ethers of oily, yield 83%.
1H?NMR(300MHz,CDCl
3）δ1.20（m,6H）,3.25（s,3H）,3.79(s,3H),4.15(m,4H),4.40(m,1H),7.05(m,2H),7.15(m,2H)。
Obtaining after compound 1, the present embodiment has adopted following four-step reaction to complete the synthetic of AMPPD.
Step a.[(3-p-methoxy-phenyl) methoxyl group methene alkane] diamantane 2 synthetic
By 3-methoxyl group-1-(1 '-p diethylaminobenzoic acid ester group) 1144 grams of benzyl methyl ethers (0.5mol), be dissolved in methyl tertiary butyl ether 400mL (in other embodiments, methyl tertiary butyl ether replaces with isopyknic isopropyl ether, ether, tetrahydrofuran (THF) and 1, any in 4-dioxane), at-75 ℃ ~-50 ℃, add LHMDS(0.5mol) and (75 grams of 2-diamantane ketone, mixing solutions 0.5mol) (in other embodiments, LHMDS such as replaces with at the LDA of amount of substance, n-Butyl Lithium, tert-butyl lithium, potassium tert.-butoxide, any in sodium tert-butoxide and sodium hydride, add the temperature of LHMDS to be controlled at-80 ℃ ~ 10 ℃), after adding, naturally rise to after room temperature, react 10 hours.Add the hydrochloric acid of 2M to make system pH in 4.0 ~ 6.5, separate organic layer dry, obtain 138 grams of target compounds after revolving desolventizing, productive rate 97%, is directly used in the next step.
Step b.[(3-hydroxy phenyl) methoxyl group methene alkane] diamantane 3 synthetic
[(3-p-methoxy-phenyl) methoxyl group methene alkane] diamantane 271 grams (0.25mol) is dissolved in the DMF of 150mL (in other embodiments, DMF replaces with isopyknic DMSO or THF), under normal temperature, drip the tetrahydrofuran solution 500mL(of sulfur alcohol sodium (0.30mol) in other embodiments, sulfur alcohol sodium is 0.9:1 ~ 3:1 with the amount of substance ratio of [(3-p-methoxy-phenyl) methoxyl group methene alkane] diamantane 2, when the amount of substance of sulfur alcohol sodium and [(3-p-methoxy-phenyl) methoxyl group methene alkane] diamantane 2 reacted and can reach an optimum effect than time in the scope at 1.05:1 ~ 2:1), after finishing, react 10 hours (in other embodiments at 100 ℃ ~ 140 ℃, temperature of reaction is controlled at 50 ℃ ~ 190 ℃).Add saturated NH to reaction solution
4cl, separates organic layer and adds anhydrous sodium sulfate drying.After revolving desolventizing, obtain yellow solid, alcohol-water recrystallization obtains 49 grams of white solids, 73%.
1H?NMR（300MHz,CDCl
3）δ1.74-1.96（m,12H）,2.62（m,1H）,3.24(m,1H),3.31（s,3H）,6.98-7.06(m,2H),7.14-7.21(m,2H)。
Synthesizing of step c [(3-phosphoric acid phenyl) methoxyl group methene alkane] diamantane disodium salt 4
By 23 grams of POCl
3(0.15mol) be dissolved in 200mL tetrahydrofuran (THF) (in other embodiments, tetrahydrofuran (THF) replaces with any in isopyknic acetonitrile, methyl tertiary butyl ether and methylene dichloride), add successively [(3-hydroxy phenyl) methoxyl group methene alkane] diamantane 327 grams (0.10mol) and pyridine 24 grams (0.30mol) (in other embodiments, pyridine such as replaces with at any in triethylamine, diisopropyl ethyl amine and the DMAP of amount of substance), react 2 hours.Add 3-hydroxypropionitrile 21 grams (0.30mol) to stir 12 hours.Add after saturated ammonium chloride solution, separate organic layer dry, revolve after desolventizing, the intermediate obtaining is dissolved in 100mL methyl alcohol, add NaOH solution (0.20mol) stirring reaction 12 hours (in other embodiments, NaOH such as replaces with at any in sodium carbonate, sodium bicarbonate and the sodium hydride of amount of substance) of 2M.After revolving desolventizing, use methanol-water recrystallization, obtain 32 grams of white solids, productive rate 81%.
1H?NMR(300MHz,CDCl
3）δ1.77－1.95（m,12H）,2.59（m,1H）,3.20(m,1H),3.30（s,3H）,6.99－7.16(m,4H)。
Steps d .AMPPD's is synthetic
[(3-phosphoric acid phenyl) methoxyl group methene alkane] diamantane disodium salt 439.4 grams (0.10mol) is dissolved in 50mL water, add 0.2 gram of methylene blue to stir (in other embodiments, methylene blue replaces with Methylene blue, any in tropeolin-D and methyl red, [(3-phosphoric acid phenyl) methoxyl group methene alkane] diamantane disodium salt 4 is 100:10 ~ 100:0.001 with the weight feed ratio of methylene blue, when time in the weight feed ratio of [(3-phosphoric acid phenyl) methoxyl group methene alkane] diamantane disodium salt 4 and the methylene blue scope at 100:5 ~ 100:0.1 react can reach an optimum effect), pass into Oxygen Flow.With 800W high-pressure mercury lamp photograph, after 1 hour (in other embodiments, high-pressure mercury lamp replaces with high voltage mercury lamp, and power range is 200W ~ 2000W), suction filtration is removed methylene blue, and decolorizing with activated carbon obtains colourless transparent liquid.After revolving desolventizing, obtain faint yellow solid, obtain 35 grams of white solid AMPPD, productive rate 82% with methanol-water recrystallization.
1H?NMR（300MHz,CDCl
3）δ1.75－1.99（m,12H）,2.63（m,1H）,3.27(m,1H),3.32（s,3H）,7.05－7.25(m,4H)。In Figure of description, the nuclear magnetic spectrogram that Fig. 1 is AMPPD, the infrared spectrogram that Fig. 2 is AMPPD.
Above-described embodiment, from low-cost m-methoxybenzaldehyde, greatly reduces cost; In synthetic route, improve the method for phosphorylation, improved the productive rate of phosphorylation reaction; In synthetic route, do not relate to strict anhydrous and oxygen-free operation, in building-up process, reaction yield is all very high, and synthetic total recovery is 36%, thereby the applicable industrial production of the present invention, has solved existing market synthetic route and has been difficult for amplifying the shortcoming of producing.
It should be noted that; above-described embodiment only as to preferred embodiment of the present invention illustrate; can not be interpreted as limitation of the present invention; all equivalent variations or replacement that all those of ordinary skill in the art make under the prerequisite without prejudice to spirit of the present invention, within the protection domain that is all considered as limiting in claim of the present invention.
Claims (10)
1. for a synthetic method of the chemical illuminating reagent AMPPD of immunoassay, it is characterized in that: the method synthetic route is as follows:
Wherein, in compound 1, R group is methyl or ethyl;
Concrete synthesis step is as follows:
Step a, condensation reaction: in ether solvent, under the effect of alkali, there is condensation reaction with 2-diamantane ketone and obtain compound 2 in compound 1, alkali is any in LDA, LHMDS, n-Butyl Lithium, tert-butyl lithium, potassium tert.-butoxide, sodium tert-butoxide and sodium hydride, while adding alkali, the temperature of system is-80 ℃ ~ 10 ℃, ether solvent is any in methyl tertiary butyl ether, isopropyl ether, ether, tetrahydrofuran (THF) and Isosorbide-5-Nitrae-dioxane;
Step b, demethylating reaction: compound 2 reacts and obtains compound 3 with sulfur alcohol sodium under heating condition, sulfur alcohol sodium is with the amount of substance of compound 2 than being 3:1 ~ 0.9:1, and temperature of reaction is 50 ℃ ~ 190 ℃, and reaction solvent is any in DMF, DMSO and THF;
Step c, phosphorylation reaction: compound 3 and 3-hydroxypropionitrile phosphorylation under the effect of acid binding agent, the solvent of phosphorylation process is any in acetonitrile, tetrahydrofuran (THF), acetonitrile, methyl tertiary butyl ether and methylene dichloride, acid binding agent is any in pyridine, triethylamine, diisopropyl ethyl amine and DMAP, and the mineral alkali when hydrolysis of di(2-ethylhexyl)phosphate propionitrile ester is any in NaOH, sodium carbonate, sodium bicarbonate and sodium hydride;
Steps d, photooxidation reaction: compound 4, under the effect of photooxidation catalyst, is reacted and obtained final product AMPPD by rayed; Light source is high-pressure mercury lamp or the high voltage mercury lamp of power at 200W ~ 2000W, and photooxidation catalyst is any in Methylene blue, methylene blue, tropeolin-D and methyl red, and compound 4 is 100:10 ~ 100:0.001 with the weight feed ratio of catalyzer.
2. according to claim 1 for the synthetic method of the chemical illuminating reagent AMPPD of immunoassay, it is characterized in that: described compound 1 is synthetic by following method:
R=methyl, ethyl
First there is acetalation: m-methoxybenzaldehyde 5 does under solution, acid catalyzed effect and reacts and obtain compound 6 with methyl alcohol with trimethyl orthoformate, the volume ratio of methyl alcohol and trimethyl orthoformate is 0.1:1 ~ 1:0.1, acid is any in the vitriol oil, concentrated hydrochloric acid, phosphoric acid, acetic acid, p-methyl benzenesulfonic acid monohydrate, ammonium chloride, tartrate and citric acid, m-methoxybenzaldehyde 5 is with sour amount of substance than being 1:0.01 ~ 1:0.5, and this step temperature of reaction is 20 ℃ ~ 95 ℃;
There is again substitution reaction: compound 6 obtains compound 1 with phosphorous acid ester under the katalysis of Lewis acid, and phosphorous acid ester is triethyl-phosphite or trimethyl phosphite.Lewis acid is any in Zinc Chloride Anhydrous, boron trifluoride diethyl etherate, boron trichloride, aluminum trichloride (anhydrous) and FERRIC CHLORIDE ANHYDROUS, and while adding Lewis acid, the temperature of system is-30 ℃ ~ 40 ℃.
3. synthetic method according to claim 2, it is characterized in that: in the acetalation step of synthetic described compound 1, the volume ratio of methyl alcohol and trimethyl orthoformate is 0.9:1 ~ 1.26:1, acid is any in the vitriol oil, acetic acid and p-methyl benzenesulfonic acid monohydrate, m-methoxybenzaldehyde is with sour amount of substance than being 1:0.1, and temperature of reaction is 65 ℃ ~ 80 ℃.
4. synthetic method according to claim 2, is characterized in that: in the substitution reaction step of synthetic described compound 1, Lewis acid is Zinc Chloride Anhydrous or boron trifluoride diethyl etherate, and the temperature that Lewis acid adds fashionable system is-20 ℃ ~-5 ℃.
5. synthetic method according to claim 2, is characterized in that: in the acetalation step of synthetic described compound 1, acid is acetic acid, and the volume ratio of methyl alcohol and trimethyl orthoformate is 1:1; In the substitution reaction step of synthetic described compound 1, phosphorous acid ester is triethyl-phosphite, and Lewis acid is Zinc Chloride Anhydrous.
6. synthetic method according to claim 1 and 2, is characterized in that: in described step a, alkali is LDA or LHMDS, and while adding alkali, the temperature of system is-75 ℃ ~-50 ℃, and reaction solvent is methyl tertiary butyl ether or tetrahydrofuran (THF).
7. synthetic method according to claim 1 and 2, is characterized in that: in described step b, sulfur alcohol sodium is with the amount of substance of compound 2 than being 1.05:1 ~ 2:1, and temperature of reaction is 100 ℃ ~ 140 ℃.
8. synthetic method according to claim 1 and 2, is characterized in that: in described step c, the solvent of phosphorylation process is that tetrahydrofuran (THF), acid binding agent are pyridine or triethylamine.
9. synthetic method according to claim 1 and 2, is characterized in that: the high-pressure mercury lamp that in described steps d, light source is 800W, and photooxidation catalyst is methylene blue, compound 4 is 100:5 ~ 100:0.1 with the weight feed ratio of methylene blue.
10. synthetic method according to claim 1 and 2, is characterized in that: in described step a, alkali is LHMDS, and reaction solvent is methyl tertiary butyl ether; In described step b, sulfur alcohol sodium is with the amount of substance of compound 2 than being 1.2:1, and reaction solvent is DMF; In described step c, the solvent of phosphorylation process is that tetrahydrofuran (THF), alkali are pyridine, and the mineral alkali when hydrolysis of di(2-ethylhexyl)phosphate propionitrile ester is NaOH; In described steps d, compound 4 is 197:1 with the weight feed ratio of methylene blue.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104597233A (en) * | 2014-11-05 | 2015-05-06 | 深圳市美凯特科技有限公司 | Enhancement solution for chemiluminiscence enhancement and chemiluminescent solution preparation method |
| CN105085569A (en) * | 2015-08-27 | 2015-11-25 | 苏州亚科化学试剂股份有限公司 | Preparation method of 1, 2-dioxetane derivative |
| CN106588990A (en) * | 2016-12-06 | 2017-04-26 | 四川沃文特生物技术有限公司 | 1,2-dioxetane derivative and preparation method thereof |
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| CN105085569B (en) * | 2015-08-27 | 2018-07-31 | 苏州亚科科技股份有限公司 | A kind of preparation method of 1,2- dioxanes derivative |
| CN106588990A (en) * | 2016-12-06 | 2017-04-26 | 四川沃文特生物技术有限公司 | 1,2-dioxetane derivative and preparation method thereof |
| CN106588990B (en) * | 2016-12-06 | 2019-02-26 | 四川沃文特生物技术有限公司 | A kind of 1,2- dioxane derivative and preparation method thereof |
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