CN102030779A - Preparation method of chemiluminescence material AMPPD (4-methoxy-4-(3-phenylphosphonic)spiro[1,2-dioxetane-3,2'-adamantane]disodium salt) for immunoassay - Google Patents
Preparation method of chemiluminescence material AMPPD (4-methoxy-4-(3-phenylphosphonic)spiro[1,2-dioxetane-3,2'-adamantane]disodium salt) for immunoassay Download PDFInfo
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- CN102030779A CN102030779A CN 201010547740 CN201010547740A CN102030779A CN 102030779 A CN102030779 A CN 102030779A CN 201010547740 CN201010547740 CN 201010547740 CN 201010547740 A CN201010547740 A CN 201010547740A CN 102030779 A CN102030779 A CN 102030779A
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Abstract
The invention relates to a preparation method of chemiluminescence material AMPPD for immunoassay, in particular to a preparation method of chemiluminescence material AMPPD (4-methoxy-4-(3-phenylphosphonic)spiro[1,2-dioxetane-3,2'-adamantane]disodium salt). 2-Adamantanone and 3-hydroxybenzoate are catalyzed in the presence of novel catalytic systems to form a double bond to obtain the key intermediate, namely substituted phenylmethoxy-methylene adamantane, and the AMPPD is obtained through the conventional photooxidation reaction. The AMPPD can be used as the illuminant in immunochemical luminescence analysis. The three catalytic systems used in the invention are all common products which are prepared in large scale and have low danger coefficient. The intermediate obtained is high in yield, and process enlargement and industrialization can be realized more easily. The AMPPD prepared in the invention can be used in the fields of reproductive hormone, thyroid hormone, anemia, cardiovascular systems, adrenal gland/hypophysis, tumor markers, infectious diseases, diabetes, hypersensitivity diseases, therapeutic drug monitoring, bone metabolism, blood virus HIV (human immunodeficiency virus) and the like.
Description
Technical field
The present invention relates to a kind of immunoassay is 4-methoxyl group-4-(3-phosphoric acid acyl phenyl with chemiluminescent substance AMPPD) spiral shell [1,2-dioxane-3,2 '-diamantane], the preparation method of disodium salt (hereinafter to be referred as AMPPD).
Background technology
AMPPD is the crucial chemical luminous substrate that uses on the full-automatic chemical luminescence immunoassay instrument, can send the very high optical signal of intensity, be widely used as chemiluminescence immune assay at present, it is stable to have the highest detection sensitivity, detected result, good reproducibility 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.
Chinese patent (patent No. CN200510021054) has been reported with 3-dimethyl tertiary butyl siloxy-1-(1 '-p diethylaminobenzoic acid ester group)-benzyl methyl ether and 2-diamantane ketone are feedstock production AMPPD; United States Patent (USP) (the patent No. 4956477; United States Patent (USP), the patent No. 6417380; United States Patent (USP), the patent No. 6124478) be feedstock production AMPPD with the prussiate of diamantane and the grignard reagent of substituted benzene.These two kinds of method yields are lower, add that intermediate preparation will carry out polystep reaction, and separation and purification is difficulty comparatively, and cost is higher.Above-mentioned China and United States Patent (USP) complicated process of preparation, reaction process had 7 steps altogether, wherein used grignard reagent, and complicated operation is produced danger, and yield is lower, is difficult to accomplish scale production.
European patent (patent No. EP0518387) is that feedstock production goes out the firm alkane of key intermediate substituted-phenyl methoxyl group methene fund by 2-diamantane ketone and 3-methyl hydroxybenzoate at metallic compound, photoxidation by routine prepares AMPPD(and sees formula one then), this reaction method flow process is short, the yield height, but the used crucial catalyzer of preparation key intermediate is to finish reaction with the catalyst system that Li-Al hydrogen/anhydrous titanous chloride is formed, but anhydrous titanous chloride performance is active, belong to spontaneously combustible, meet burning of air and water or blast, the tool strong and stimulating is to mucous membrane, the upper respiratory tract, eye and skin have strong impulse.After the suction, can be because of larynx and bronchial spasm, inflammation, oedema, chemical pneumonitis or pulmonary edema and cause death.Cause burning sensation after the contact, cough, pant, laryngitis, breathe hard, have a headache, feel sick, vomiting etc., have not yet to see large-scale production, also do not have the supply of commodities of mass-producing.
Summary of the invention
The purpose of this invention is to provide the preparation method of a kind of immunoassay with chemiluminescent substance AMPPD, is the new synthetic method of AMPPD.Obtain the firm alkane of key intermediate substituted-phenyl methoxyl group methene fund by new catalyst system, the photooxidation reaction by routine obtains AMPPD then.The AMPPD that the present invention makes can be widely used as the shiner of immunochemiluminometry.Can be used for fields such as reproductive hormone, Triiodothyronine, anaemia, cardiovascular systems, suprarenal gland/hypophysis, tumor markers, infectious diseases, diabetes, anaphylactic disease, medicine monitoring, bone metabolism, blood disease HIV.
The present invention forms two keys and obtains the firm alkane of key intermediate substituted-phenyl methoxyl group methene fund with 2-diamantane ketone and 3-methyl hydroxybenzoate under the catalysis of new catalyst system, the photooxidation reaction by routine obtains AMPPD(and sees formula two then):
New catalyst system of the present invention is meant by the extensive dangerous little anhydrous titanium tetrachloride (TiCl of commercialization
4) with Li-Al hydrogen (LAH), metallic zinc (Zn) or metallic tin (Sn) three in a kind of separately or common two components or the polycomponent catalyst system of forming that use, wherein the chemical mol ratio of the consumption of titanium tetrachloride and Li-Al hydrogen, metallic zinc or metallic tin is 1:1-10, be preferably 1:1-5, concrete catalyst system is: TiCl
4/ LAH, TiCl
4/ Zn, TiCl
4Three kinds of/Sn.
Three general goods that catalyst system all is large-scale production that the present invention uses, and the dangerous end, the intermediate yield height that obtains is than being easier to realize technology amplification and industrialization.
Embodiment
Embodiments of the invention are as follows:
One, the preparation of [(3-hydroxy phenyl) methoxyl group methene alkane] diamantane
Embodiment 1:TiCl4/Zn catalyst system
Anhydrous and oxygen-free operation (high pure nitrogen protection): join in the 5000ml there-necked flask and stir and dropping funnel, fully replace nitrogen, adding 2000mlTHF(will handle), be cooled to the 0-10 degree in the ice, add the anhydrous titanium tetrachloride of 190 grams (molecular weight: 189 fast.71) (1mmol), in 10 degree, add 65 gram zinc powder (molecular weight 65 in batches.39), rise to room temperature, reflux 2 hours (nitrogen protection) progressively then, cool to room temperature adds triethylamine 101 gram (1mmol) (density 0.7, molecular weight 101.19) (do no water treatment), refluxed 1 hour, dripped 3-methyl hydroxybenzoate (molecular weight 152 then at 90 minutes under the internal reflux state.15, fusing point 70-72) 30 grams (0.2mmol) (thorough drying) and 2-diamantane ketone (molecular weight: 150.22) 60 grams (0.2mmol) the 500mlTHF mixing solutions of (thorough drying) adds the back and continues to reflux 1 hour, drips 2-diamantane ketone (molecular weight: 150 then in 30 minutes.22) 30 grams (0.50mlTHF solution 2mmol) is cooled to 10 degree down, adds 4000ml water (slowly, temperature is no more than 15 degree), use the 4X500ml ethyl acetate extraction, wash drying with water and concentrated silica gel (15% ethyl acetate/petroleum ether) and obtain white solid 45 gram, fusing point 133-134 degree.
1H NMR（300MHz,?CDCl
3）:δ1.64-1.96(M,12H),2.65(S,1H),3.24(S,1H),3.32(S,3H),6.7-7.3(M,4H)。
Embodiment 2:TiCl4/LAH catalyst system
Anhydrous and oxygen-free operation (high pure nitrogen protection): join in the 5000ml there-necked flask and stir and dropping funnel, fully replace nitrogen, adding 2000mlTHF(will handle), be cooled to the 0-10 degree in the ice, add the anhydrous titanium tetrachloride of 190 grams (molecular weight: 189 fast.71) (1mmol), in 10 degree, add the LAH(Li-Al hydrogen in batches) 76 gram (molecular weight 37.95), rise to room temperature, reflux 2 hours (nitrogen protection) progressively then, cool to room temperature adds triethylamine 202 gram (2mmol) (density 0.7, molecular weight 101.19) (do no water treatment), refluxed 1 hour, dripped 3-methyl hydroxybenzoate (molecular weight 152 then at 90 minutes under the internal reflux state.15, fusing point 70-72) 30 grams (0.2mmol) (thorough drying) and 2-diamantane ketone (molecular weight: 150.22) 60 grams (0.2mmol) the 500mlTHF mixing solutions of (thorough drying) adds the back and continues to reflux 1 hour, drips 2-diamantane ketone (molecular weight: 150 then in 30 minutes.22) 30 grams (0.50mlTHF solution 2mmol) is cooled to 10 degree down, adds 4000ml water (slowly, temperature is no more than 15 degree), use the 4X500ml ethyl acetate extraction, wash drying with water and concentrated silica gel (15% ethyl acetate/petroleum ether) and obtain white solid 30 gram, fusing point 133-134 degree.
1H NMR（300MHz,?CDCl
3）:δ1.64-1.96(M,12H),2.65(S,1H),3.24(S,1H),3.32(S,3H),6.7-7.3(M,4H)。
Embodiment 3:TiCl4/Sn catalyst system
Anhydrous and oxygen-free operation (high pure nitrogen protection): join in the 5000ml there-necked flask and stir and dropping funnel, fully replace nitrogen, adding 2000mlTHF(will handle), be cooled to the 0-10 degree in the ice, add the anhydrous titanium tetrachloride of 190 grams (molecular weight: 189 fast.71) (1mmol), in 10 degree, add 160 gram glass puttys (molecular weight 118.69) in batches, rise to room temperature, reflux 2 hours (nitrogen protection) progressively then, cool to room temperature adds triethylamine 101 gram (1mmol) (density 0.7, molecular weight 101.19) (do no water treatment), refluxed 1 hour, dripped 3-methyl hydroxybenzoate (molecular weight 152 then at 90 minutes under the internal reflux state.15, fusing point 70-72) 30 grams (0.2mmol) (thorough drying) and 2-diamantane ketone (molecular weight: 150.22) 60 grams (0.2mmol) the 500mlTHF mixing solutions of (thorough drying) adds the back and continues to reflux 1 hour, drips 2-diamantane ketone (molecular weight: 150 then in 30 minutes.22) 30 grams (0.50mlTHF solution 2mmol) is cooled to 10 degree down, adds 4000ml water (slowly, temperature is no more than 15 degree), use the 4X500ml ethyl acetate extraction, wash drying with water and concentrated silica gel (15% ethyl acetate/petroleum ether) and obtain white solid 50 gram, fusing point 133-134 degree.
1H NMR（300MHz,?CDCl
3）:δ1.64-1.96(M,12H),2.65(S,1H),3.24(S,1H),3.32(S,3H),6.7-7.3(M,4H)。
Two, the preparation of [(3-phosphoric acid phenyl) methoxyl group methene alkane] diamantane disodium salt
With the 3rd step product (500 g; 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 the assorted CH of usefulness 5X30
2Cl
2Wash, in refrigerator, spend the night after the cooling, from the aqueous solution, be settled out product, with the assorted cold water washing solid product of 3X10, with this white solid drying under reduced pressure, obtain the 360g product then earlier, 1H NMR 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).
Three, spiral shell [1,2-dioxane-3,2 '-diamantane] 4-methoxyl group-4-(3-phosphoric acid acyl phenyl), the preparation of disodium salt (AMPPD) salt
Adopt 1000 watts high-pressure mercury lamp, at 300ml H
2In the O/P-diox (1:1V/V), in 10
oC, with the 3rd step product 20g dissolving, logical oxygen carries out photooxidation reaction, steams solvent after having reacted and gets head product, gets product 16g behind the recrystallization.
1H?NMR ：δ?0.91-1.70（m,12H）,2.08(s,1H),2.80(s,1H),3.07(s,3H),7.00-7.26(m,4H)。
Claims (2)
1. an immunoassay is with the preparation method of chemiluminescent substance, particularly immunoassay is with chemiluminescent substance 4-methoxyl group-4-(3-phosphoric acid acyl phenyl) spiral shell [1,2-dioxane-3,2 '-diamantane], the preparation method of disodium salt AMPPD, it is characterized in that: this method forms two keys and obtains the firm alkane of key intermediate substituted-phenyl methoxyl group methene fund with 2-diamantane ketone and 3-methyl hydroxybenzoate under the catalysis of new catalyst system, photooxidation reaction by routine obtains AMPPD then, described new catalyst system is meant by extensive dangerous little anhydrous titanium tetrachloride and Li-Al hydrogen of commercialization, a kind of two components or polycomponent catalyst system of forming that use separately or jointly among metallic zinc or the metallic tin three, wherein titanium tetrachloride and Li-Al hydrogen, the chemical mol ratio of the consumption of metallic zinc or metallic tin is 1:1-10, and concrete catalyst system is: TiCl
4/ LAH, TiCl
4/ Zn, TiCl
4Three kinds of/Sn.
2. immunoassay as claimed in claim 1 is characterized in that with the preparation method of chemiluminescent substance AMPPD: the chemical mol ratio of the consumption of titanium tetrachloride and Li-Al hydrogen, metallic zinc or metallic tin is 1:1-5 in the described new catalyst system.
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Cited By (5)
| 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 |
| CN103073589A (en) * | 2012-12-30 | 2013-05-01 | 杭州师范大学 | Synthetic method of 1, 2-dioxetane compound |
| CN103204758A (en) * | 2012-12-17 | 2013-07-17 | 湖北航天化学技术研究所 | Tetracyclic decene dimer synthesis method |
| CN105445452A (en) * | 2015-11-17 | 2016-03-30 | 苏州浩欧博生物医药有限公司 | Anti-gp210 antibody test kit and testing method thereof |
| CN116813662A (en) * | 2023-05-09 | 2023-09-29 | 研峰科技(北京)有限公司 | Synthesis process of titanium trichloride tetrahydrofuran compound (1:3) |
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| CN1040980A (en) * | 1988-07-27 | 1990-04-04 | 韦恩州立大学校董会 | Improve 1, the composition of the method for 2-dioxane chemoluminescence effect |
| CN1052478A (en) * | 1989-12-14 | 1991-06-26 | 书恩州立大学校董会 | Improving one's methods of preparation vinyl ether |
| WO1997000849A1 (en) * | 1995-06-20 | 1997-01-09 | Lumigen, Inc. | Novel vinyl sulfide compounds and a process for their preparation |
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2010
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1040980A (en) * | 1988-07-27 | 1990-04-04 | 韦恩州立大学校董会 | Improve 1, the composition of the method for 2-dioxane chemoluminescence effect |
| CN1052478A (en) * | 1989-12-14 | 1991-06-26 | 书恩州立大学校董会 | Improving one's methods of preparation vinyl ether |
| WO1997000849A1 (en) * | 1995-06-20 | 1997-01-09 | Lumigen, Inc. | Novel vinyl sulfide compounds and a process for their preparation |
Cited By (7)
| 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 |
| CN103204758A (en) * | 2012-12-17 | 2013-07-17 | 湖北航天化学技术研究所 | Tetracyclic decene dimer synthesis method |
| CN103204758B (en) * | 2012-12-17 | 2014-11-26 | 湖北航天化学技术研究所 | Tetracyclic decene dimer synthesis method |
| CN103073589A (en) * | 2012-12-30 | 2013-05-01 | 杭州师范大学 | Synthetic method of 1, 2-dioxetane compound |
| CN105445452A (en) * | 2015-11-17 | 2016-03-30 | 苏州浩欧博生物医药有限公司 | Anti-gp210 antibody test kit and testing method thereof |
| CN116813662A (en) * | 2023-05-09 | 2023-09-29 | 研峰科技(北京)有限公司 | Synthesis process of titanium trichloride tetrahydrofuran compound (1:3) |
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Application publication date: 20110427 |