CN1876663A - Chemiluminescent reagent 4-methox-4-(3-phosphorylphenyl)spiro[1,2- dioxycyclohexane-3,2'- adamantane], disodium salt synthesis method - Google Patents
Chemiluminescent reagent 4-methox-4-(3-phosphorylphenyl)spiro[1,2- dioxycyclohexane-3,2'- adamantane], disodium salt synthesis method Download PDFInfo
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- CN1876663A CN1876663A CN 200510021054 CN200510021054A CN1876663A CN 1876663 A CN1876663 A CN 1876663A CN 200510021054 CN200510021054 CN 200510021054 CN 200510021054 A CN200510021054 A CN 200510021054A CN 1876663 A CN1876663 A CN 1876663A
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- amppd
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Abstract
The invention relates the preparing method of chemiluminescence agent, especially the 4- methoxy- 4- (3- phosphoryl acyl phenyl) tap bolt [1, 2- epoxyethane- 3, 2'- adamantine], AMPPD. The method comprises the following steps: using 3- dimethyl tertiary-butyl silica- 1- (1'- phosphate diethyl ester) benzyl dimethyl ether and 2- adamantine as raw material, carrying out Wittig reaction, getting [(3- dimethyl tertiary-butyl silica) methoxyl methane alkyl] adamantine, carrying out photo-oxidation, and getting [(3- phosphate phenyl) methoxyl methane alkyl] adamantine (AMPPD).
Description
The present invention relates to the novel preparation method of chemical illuminating reagent, 4-methoxyl group-4-(3-phosphoric acid acyl phenyl) spiral shell [1,2-dioxane-3,2 '-diamantane] particularly, the new synthetic method of disodium salt (hereinafter to be referred as AMPPD).
AMPPD is the chemical luminous substrate of alkaline phosphatase, and in suitable damping fluid, along with the catalytic hydrolysis effect of enzyme, AMPPD resolves into AMP-D, and the latter sends the very high optical signal of intensity, and its luminous speed depends on the concentration of alkali phosphorus enzyme.When alkali phosphorus enzyme is coupled to the probe of hybridization, just can detect the amount of hybrid molecule by this system.Be widely used as at present the luminous substrate of chemiluminescence immune assay, have the highest detection sensitivity, be applicable to the material that detects various molecular weight, stable luminous substrate, detected result be stable, good reproducibility, detect linear wide ranges, do not need special luminous substrate-antigen/antibody connector, convenience, use easily, can to use multiple analytical model (sandwich, unexpectedly strive, antibody tests etc.) etc. advantage is medically being promoted the use of.But, limited its large-scale development and used because its price is higher.The major cause that price is high is a comparatively difficulty of this material preparation, the synthesis technique complexity.
Its preparation at present mainly contains two lines, first kind is to form two keys by 2-diamantane ketone and 3-methyl hydroxybenzoate under the catalysis of metallic compound to obtain the firm alkane of key intermediate substituted-phenyl methoxyl group methene fund, photooxidation reaction by routine obtains AMPPD (seeing formula one) (United States Patent (USP), the patent No. 5582980 then; Chinese patent, patent No. CN 1040980A), this method yield is lower, and separation and purification is difficulty comparatively.Second method is that the grignard reagent by the prussiate of diamantane and substituted benzene forms two keys and obtains the firm alkane of key intermediate substituted-phenyl methoxyl group methene fund, photooxidation reaction by routine obtains AMPPD (seeing formula two) (United States Patent (USP), the patent No. 4956477 then; United States Patent (USP), the patent No. 6417380; United States Patent (USP), the patent No. 6124478; European patent, the patent No. 0582317 etc.), this method flow is oversize, use the prussiate of severe toxicity.
(formula one)
(formula two)
The new synthetic method that the purpose of this invention is to provide a kind of chemical illuminating reagent AMPPD.React by Wittig and to form two keys and obtain the firm alkane of key intermediate substituted-phenyl methoxyl group methene fund, the photooxidation reaction by routine obtains AMPPD then.
The present invention is to be raw material with 3-dimethyl tertiary butyl siloxy-1-(1 '-p diethylaminobenzoic acid ester group)-benzyl methyl ether and 2-diamantane ketone, react by Wittig, prepare [(3-dimethyl tertiary butyl siloxy phenyl) methoxyl group methene alkane] diamantane, obtaining AMPPD by photoxidation, reaction process following (formula three):
Embodiments of the invention are as follows:
One, the preparation of 3-dimethyl tertiary butyl siloxy-1-(1 '-p diethylaminobenzoic acid ester group)-benzyl methyl ether
Again in the mixed solvent of 500 milliliters of ethanol and 50 water, stirring and dissolving adds 80 gram (1.43mol) potassium hydroxide with the dissolving of the above-mentioned product of 374 grams (1mol), and stirring and dissolving obtains settled solution.0-5 degree centigrade drips 172.8 gram (1.2mol) methyl iodide down, stir under the room temperature after 2 hours, 60 degrees centigrade were reacted 12 hours down again, after having reacted, add 1000 milliliters in water, with methyl ethyl ether extraction, merge organic phase, use 500 milliliters of the sodium hydroxide solutions of 3N successively, wash PH7, dry filter, concentrate, recrystallization obtains product 310 grams, productive rate is 80%
1H NMR ((300MHz, CDCl
3) δ 0.08 (s, 6H), 0.9 (s, 9H), 1.1 (t, 6H), 3.3 (s, 3H), 4.1 (q, 4H), 4.1 (s, 1H), 6.6-7.1 (m, 4H) .).
Two, the preparation of [(3-dimethyl tertiary butyl siloxy phenyl) methoxyl group methene alkane] diamantane
The diamantane ketone of 388 gram (1mol) above-mentioned products and 150 grams (1mol) are joined in three mouthfuls of round-bottomed flasks of 2000 milliliters successively, the exsiccant tetrahydrofuran (THF) that adds 1000 milliliters, the triethylamine that adds 51 grams again, stirring and dissolving, temperature rising reflux are after 24 hours, and the TLC detection reaction finishes, reaction solution is transferred in the round-bottomed flask, concentrating under reduced pressure removes triethylamine and solvent obtains product 234 grams, and productive rate is 61%
1H NMR (300MHz, CDCl
3) (δ 0.08 (s, 6H), 0.9 (s, 9H), 3.5 (s, 3H), 4.1 (s, 1H), 6.6-7.1 (m, 4H) .).
(formula three)
Three, the preparation of [(3-hydroxy phenyl) methoxyl group methene alkane] diamantane
38.4 gram (0.1mol) second step products are dissolved in 500 milliliters the exsiccant tetrahydrofuran (THF), drip 100 milliliters of the tetrahydrofuran solutions of the tetrabutyl ammonium fluoride of 1M then, whole system at room temperature stirred 30 minutes, pour into then in 1000 milliliters of the saturated sodium hydrogen carbonate solutions, solution 500 milliliters of extractions of methylene dichloride, organic phase water is again washed for 500 milliliters, and concentrating under reduced pressure obtains product 21.6 grams behind the anhydrous sodium sulfate drying, productive rate is 80%
1H NMR (300MHz, CDCl
3): δ 1.64-1.96 (M, 12H), 2.65 (S, 1H), 3.24 (S, 1H), 3.32 (S, 3H), 6.7-7.3 (M, 4H).
Four, the preparation of [(3-phosphoric acid phenyl) methoxyl group methene alkane] diamantane disodium salt
With the 3rd step product (500g; 1.58mol) be dissolved in the 5ml anhydrous pyridine (using the alkali alumina drying); this solution is added to slowly (1 is assorted by phosphorus oxychloride; 10.7mol) and the cooling mixture formed of 5 assorted pyridines, its feed rate should maintain temperature of reaction under 5 ℃, after 30 minutes; termination reaction; and the dichlor-phosphoryl product is poured on the mixture of being made up of 20kg ice and 1 assorted 10N sodium hydroxide, this mixture is moved in the separating funnel, with 5 * 30 assorted CH
2Cl
2Wash, in refrigerator, spend the night after the cooling, from the aqueous solution, be settled out product, with 3 * 10 assorted cold water washing solid products, with this white solid drying under reduced pressure, obtain the 360g product then earlier, 1HNMR δ: 1.67-1.83 (m, 12H), 2.50 (s, 1H), 3.04 (s, 1H), 3.19 (s.3H), 6.7-7.2 (m, 4H).Five, 4-methoxyl group-4-(3-phosphoric acid acyl phenyl) spiral shell [1,2-dioxane-3,2 '-diamantane], the preparation of disodium salt (AMPPD) salt
Adopt 1000 watts high-pressure mercury lamp, at 300ml H
2(1: 1V/V), in 10 ℃, with the 3rd step product 20g dissolving, logical oxygen carries out photooxidation reaction to the O/P-diox, steams solvent after having reacted and gets head product, gets product 16g behind the recrystallization.
1HNMR：δ0.91-1.70(m，12H)，2.08(s，1H)，2.80(s，1H)，3.07(s，3H)，7.00-7.26(m，4H)。
Claims (2)
1. the novel preparation method of a chemical illuminating reagent, particularly 4-methoxyl group-4-(3-phosphoric acid acyl phenyl) spiral shell [1,2-dioxane-3,2 '-diamantane], the new synthetic method of disodium salt (hereinafter to be referred as AMPPD).This method is reacted by Wittig and is formed two keys and obtain the firm alkane of key intermediate substituted-phenyl methoxyl group methene fund, and the photooxidation reaction by routine obtains AMPPD then.
2. the novel preparation method of chemical illuminating reagent AMPPD according to claim 1, it is characterized in that with 3-dimethyl tertiary butyl siloxy-1-(1 '-p diethylaminobenzoic acid ester group)-benzyl methyl ether and 2-diamantane ketone be raw material, react by Wittig, prepare [(3-dimethyl tertiary butyl siloxy phenyl) methoxyl group methene alkane] diamantane, obtaining [(3-phosphoric acid phenyl)] methoxyl group methene alkane by photoxidation] diamantane (AMPPD), its technology of preparing route is as follows:
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| CN 200510021054 CN1876663A (en) | 2005-06-09 | 2005-06-09 | Chemiluminescent reagent 4-methox-4-(3-phosphorylphenyl)spiro[1,2- dioxycyclohexane-3,2'- adamantane], disodium salt synthesis method |
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| CN 200510021054 CN1876663A (en) | 2005-06-09 | 2005-06-09 | Chemiluminescent reagent 4-methox-4-(3-phosphorylphenyl)spiro[1,2- dioxycyclohexane-3,2'- adamantane], disodium salt synthesis method |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875600A (en) * | 2012-09-28 | 2013-01-16 | 深圳市宝凯仑科技有限公司 | Synthetic method of 1,2-dioxetane compound |
| CN103772433A (en) * | 2012-10-18 | 2014-05-07 | 深圳市美凯特科技有限公司 | Synthetic method of chemiluminescence reagent AMPPD for immunization analysis |
| CN103951704A (en) * | 2013-12-10 | 2014-07-30 | 云南民族大学 | Preparation method of chemiluminescent compound AMPPD for immunoassay |
| 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 |
-
2005
- 2005-06-09 CN CN 200510021054 patent/CN1876663A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102875600A (en) * | 2012-09-28 | 2013-01-16 | 深圳市宝凯仑科技有限公司 | Synthetic method of 1,2-dioxetane compound |
| CN102875600B (en) * | 2012-09-28 | 2015-04-01 | 深圳市宝凯仑科技有限公司 | Synthetic method of 1,2-dioxetane compound |
| CN103772433A (en) * | 2012-10-18 | 2014-05-07 | 深圳市美凯特科技有限公司 | Synthetic method of chemiluminescence reagent AMPPD for immunization analysis |
| CN103951704A (en) * | 2013-12-10 | 2014-07-30 | 云南民族大学 | Preparation method of chemiluminescent compound AMPPD for immunoassay |
| 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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Open date: 20061213 |