CN106589029A - Preparation method of adenosine cyclophosphate tripolymer impurity - Google Patents
Preparation method of adenosine cyclophosphate tripolymer impurity Download PDFInfo
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- CN106589029A CN106589029A CN201610966636.0A CN201610966636A CN106589029A CN 106589029 A CN106589029 A CN 106589029A CN 201610966636 A CN201610966636 A CN 201610966636A CN 106589029 A CN106589029 A CN 106589029A
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- pyridine
- adenosine cyclophosphate
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- impurity
- trimerization
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
The invention relates to a preparation method of an adenosine cyclophosphate tripolymer impurity, wherein a reaction is carried with adenosine cyclophosphate and phosphorus oxychloride as initial raw materials under the effects of a solvent and a reagent, a reaction product is then purified to obtain the adenosine cyclophosphate tripolymer impurity. The method is simple, is high in product purity, and is suitable for medicine quality researching.
Description
Technical field
The present invention relates to a kind of specific trimerization impurity of adenosine cyclophosphate and its method for preparation.
Background technology
The Formula II compound being illustrated below：Adenosine cyclophosphate, i.e.,:Ribosidoadenine -3 ', 5 '-cyclic phosphate, abbreviation cAMP,
It is one of focus of current molecular biological study.
The disease relationships such as cAMP and psoriasiss, coronary heart disease, asthma, hypertension, diabetes and malignant tumor are very close.
In the building-up process of protein, the transcription and translation of gene is all affected by cAMP.It controls hereditary information, play " the
The effect of two couriers ", and affect the activity of many enzymes and the metabolic process of cell.Therefore, research work and medical clinical test
It is both needed to substantial amounts of cAMP.Adenosine cyclophosphate is nucleotide drug, clinically, is mainly used in treating cardiac insufficiency, angina pectoriss
And myocardial infarction, it is particularly suited for the poisoning of digitalis cardiac tonic or insensitive patient.
But as the country is for the day by day attention of imitation medicine quality, it is desirable to carry out the quality conformance evaluation of imitation medicine,
Grinding medicine with state exogenesis carries out comparative study.The particularly important is the impurity spectrum to medicine carries out system, comprehensively researchs and analyses,
And contamination levels product are the materials that must possess during drug research.Therefore impurity research is conducive to improving for medicinal substances
Amount, the safe and effective utilization medicine for the people provides help.
From the eighties of last century five, sixties, just there are successively the synthesis of document report adenosine cyclophosphate in foreign countries.Subsequently, it is a series of
Process be increasingly being used to produce adenosine cyclophosphate, mainly have alkaline trimerization method, active esters method, DCC evaporations and trichlorine
Four kinds of oxygen phosphorus method etc..But for the trimerization impurity of adenosine cyclophosphate, lacking has researcher.
Pharmacological research shows that adenosine cyclophosphate, being capable of selectivity retardance as a kind of newest Horizon class antihypertensive drug
Calcium ion, induction calcium ion flowing, reduces intracellular calcium concentration, reduces the tension force of vascular smooth muscle and its endogenouss are added
The reaction of pressure material, so as to vasodilator, reduces blood pressure.This product is injectable emulsion, for reducing unsuitable oral medication or mouth
The hypertension failed to respond to any medical treatment of clothes, rapid-action, effect eliminates also fast, can ascending-dose accurately control blood pressure.With current many Jing
The antihypertensive used for intravenous injection of kidney and (or) hepatic metabolism is different, adenosine cyclophosphate metabolism in blood and tissue, thus does not exist
Body accumulation.
It is domestic more for the Study of synthesis method of adenosine cyclophosphate, but prepared by less research to its impurity, and it is current
Medicine declares higher for the requirement of impurity research.
Therefore, research and develop a kind of easy to operate, product purity higher, and be suitable for the adenosine cyclophosphate trimerization of drug quality research
The preparation method of impurity is necessary.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of adenosine cyclophosphate trimerization impurity, the preparation method
Easy to operate, product purity is higher, and is suitable for drug quality research.
To solve above-mentioned technical problem, the technical scheme is that：One kind is such as formula (I)：
The preparation method of shown adenosine cyclophosphate trimerization impurity, its innovative point is：The preparation method is with adenosine cyclophosphate
It is initiation material with phosphorus oxychloride, is reacted in the presence of solvent and reagent, reacted product is purified again obtains formula
(I) the adenosine cyclophosphate trimerization impurity shown in；The reaction equation is：
Further, described solvent is phosphoric acid ester, halophosphorus compound, pyridine or pyridine compounds and their, triethylamine
Or other organic amine compounds, tetrahydrofuran, benzene, dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, 1,4- dioxies
Six rings, acetone, butanone, ethyl acetate, butyl acetate, propyl acetate, acetonitrile, propionitrile, N,N-dimethylformamide, dimethyl are sub-
Sulfone, acetic acid, propanoic acid, preferably phosphoric acid esters, halo phosphine compound, pyridine or pyridine compounds and their, triethylamine or other organic amines
One or more, particularly preferred triethyl phosphate in class compound.
Further, described reagent is pyridine or pyridine compounds and their, triethylamine or other organic amine compounds, or
Person's potassium carbonate, sodium carbonate inorganic alkaline compound or its mixture, preferred pyridine or pyridine compounds and their, particularly preferred pyrrole
Pyridine.
Further, described reaction temperature is -10～200 DEG C, and preferred reaction is 70～90 DEG C.
It is an advantage of the current invention that：Preparation method of the present invention is easy to operate, product purity is higher, and is suitable for drug quality
Research.
Specific embodiment
The following examples can make professional and technical personnel that the present invention is more fully understood, but not therefore by this
It is bright to be limited among described scope of embodiments.
The present invention is such as formula (I)：
The preparation method of shown adenosine cyclophosphate trimerization impurity, the preparation method is with ring phosphorus gland
Glycosides and phosphorus oxychloride are initiation material, are reacted in the presence of solvent and reagent, instead
Should after the product purified adenosine cyclophosphate trimerization impurity obtained shown in formula (I) again；It is described
Reaction equation is：
Used as the present invention, more specifically embodiment is that solvent is phosphoric acid ester, halophosphorus compound, pyridine or pyridines
Compound, triethylamine or other organic amine compounds, tetrahydrofuran, benzene, dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloros
Ethane, 1,4- dioxane, acetone, butanone, ethyl acetate, butyl acetate, propyl acetate, acetonitrile, propionitrile, N, N- dimethyl methyls
Amide, dimethyl sulfoxide, acetic acid, propanoic acid, preferably phosphoric acid esters, halo phosphine compound, pyridine or pyridine compounds and their, triethylamine
Or one or more in other organic amine compounds, particularly preferred triethyl phosphate.
Reagent is pyridine or pyridine compounds and their, triethylamine or other organic amine compounds, or potassium carbonate, sodium carbonate
Inorganic alkaline compound or its mixture, preferred pyridine or pyridine compounds and their, particularly preferred pyridine.
Reaction temperature is -10～200 DEG C, and preferred reaction is 70～90 DEG C.
Embodiment
Adenosine cyclophosphate (8.01g, 30mmol) and phosphorus oxychloride (1.53g, 10mmol) are thoroughly mixed in round-bottomed bottle,
Triethyl phosphate (50ml) and pyridine (10ml), reactant is added to stir 4 hours at 70-90 DEG C under room temperature.Vacuum distillation goes out
Solvent is removed, then column chromatography obtains compound A for white solid (1.7g, 5mmol, 50%yield).
Spectral data：
1H NMR(500MHz,D2O)δ8.58(s,1H),8.35(s,1H),6.99(s,2H),6.16(dd,1H),4.75
(m,1H),4.51(m,1H),4.40(m,1H),4.28(m,2H),3.58(m,2H)；
MS(ESI):855.72。
The ultimate principle and principal character and advantages of the present invention of the present invention has been shown and described above.The skill of the industry
Simply explanation of the art personnel it should be appreciated that the present invention is not restricted to the described embodiments, described in above-described embodiment and description
The principle of the present invention, without departing from the spirit and scope of the present invention, the present invention also has various changes and modifications, these
Changes and improvements are both fallen within scope of the claimed invention.The claimed scope of the invention by appending claims and
Its equivalent thereof.
Claims (4)
1. one kind such as formula (I)：
The preparation method of shown adenosine cyclophosphate trimerization impurity, it is characterised in that：The preparation method is with adenosine cyclophosphate and trichlorine
Oxygen phosphorus is initiation material, is reacted in the presence of solvent and reagent, and reacted product is purified again to be obtained shown in formula (I)
Adenosine cyclophosphate trimerization impurity；The reaction equation is：
2. the preparation method of adenosine cyclophosphate trimerization impurity according to claim 1, it is characterised in that：Described solvent is phosphorus
Esters of gallic acid, halophosphorus compound, pyridine or pyridine compounds and their, triethylamine or other organic amine compounds, tetrahydrofuran,
Benzene, dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethanes, 1,4- dioxane, acetone, butanone, ethyl acetate, acetic acid fourth
Ester, propyl acetate, acetonitrile, propionitrile, DMF, dimethyl sulfoxide, acetic acid, propanoic acid, preferably phosphoric acid esters, halo
One or more in phosphine compound, pyridine or pyridine compounds and their, triethylamine or other organic amine compounds, particularly preferably
Triethyl phosphate.
3. the preparation method of adenosine cyclophosphate trimerization impurity according to claim 1, it is characterised in that：Described reagent is pyrrole
Pyridine or pyridine compounds and their, triethylamine or other organic amine compounds, or potassium carbonate, sodium carbonate inorganic alkaline compound or
Person its mixture, preferred pyridine or pyridine compounds and their, particularly preferred pyridine.
4. the preparation method of adenosine cyclophosphate trimerization impurity according to claim 1, it is characterised in that：Described reaction temperature
For -10～200 DEG C, preferred reaction is 70～90 DEG C.
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| CN201610966636.0A CN106589029A (en) | 2016-10-28 | 2016-10-28 | Preparation method of adenosine cyclophosphate tripolymer impurity |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009221168A (en) * | 2008-03-18 | 2009-10-01 | Institute Of Physical & Chemical Research | Nucleoside or nucleotide derivative, nucleic acid derivative, target substance-capturing material, method for capturing and/or releasing target substance, and hemin aptamer |
| CN102268055A (en) * | 2010-06-04 | 2011-12-07 | 南京工业大学 | Method for separating adenosine cyclophosphate |
| CN104163843A (en) * | 2014-07-15 | 2014-11-26 | 南通香地生物有限公司 | Adenosine 5'-monophosphoric acid disodium salt production method |
-
2016
- 2016-10-28 CN CN201610966636.0A patent/CN106589029A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2009221168A (en) * | 2008-03-18 | 2009-10-01 | Institute Of Physical & Chemical Research | Nucleoside or nucleotide derivative, nucleic acid derivative, target substance-capturing material, method for capturing and/or releasing target substance, and hemin aptamer |
| CN102268055A (en) * | 2010-06-04 | 2011-12-07 | 南京工业大学 | Method for separating adenosine cyclophosphate |
| CN104163843A (en) * | 2014-07-15 | 2014-11-26 | 南通香地生物有限公司 | Adenosine 5'-monophosphoric acid disodium salt production method |
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