CN105693800A - Preparation method of Cangrelor intermediate - Google Patents
Preparation method of Cangrelor intermediate Download PDFInfo
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- CN105693800A CN105693800A CN201610253038.9A CN201610253038A CN105693800A CN 105693800 A CN105693800 A CN 105693800A CN 201610253038 A CN201610253038 A CN 201610253038A CN 105693800 A CN105693800 A CN 105693800A
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- 0 *C[C@@](*[C@]1C[n]2c(N=C(*)CN=C3c4ccccc4)c3nc2)[C@](*)[C@]1O Chemical compound *C[C@@](*[C@]1C[n]2c(N=C(*)CN=C3c4ccccc4)c3nc2)[C@](*)[C@]1O 0.000 description 2
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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
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
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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 a Cangrelor intermediate as indicated in formula (I).According to the preparation method, a compound of the structure as indicated in formula (II) is adopted as the raw material, solvent and reaction reagent are added, a specific reaction is conducted, a product obtained after the reaction is then subjected to purification, and the Cangrelor intermediate as indicated in formula (I) is obtained, wherein the specific structure of formula (II) can be found in the specification. The preparation method has the advantages of being easy and convenient to operate, high in product purity, high in safety of the reaction process, suitable for industrialized production and low in cost.
Description
Technical field
The invention belongs to pharmaceutical intermediate synthesis field, particularly to a kind of cangrelor intermediate
Preparation method。
Background technology
The formula III compound being illustrated below: cangrelor, that is: Cangrelor, No. CAS: 163706-06-7。Cangrelor (Cangrelor) is a kind of intravenous antiplatelet drug, it is possible to quickly, reversibly suppress the ADP platelet aggregation induced。Different from the Thienopyridines medicine such as clopidogrel and prasugrel, cangrelor is not Thienopyridines, by drug administration by injection, directly acts on P2Y12 platelet receptor, thus playing antiplatelet effects。
Early studies in man shows, in the several seconds after cangrelor administration, hematoblastic activation and gathering are suppressed, and in stopping administration latter 60 minutes, hematoblastic functional rehabilitation, its plasma half-life is approximately 10 minutes。This medicine is succeeded in developing by Astrazeneca AB in December, 2003, later by another Medicines corporate buyout of United States pharmaceutical company of family。
Evaluating cangrelor curative effect in accepting percutaneous coronary intervention (pci) (PCI) patient has 2 III clinical trial phase: CHAMPION-PLATFORM to evaluate cangrelor and placebo phase comparison, CHAMPION-PCI research is then for comparing the relative efficacy of cangrelor and clopidogrel, and the result reached of jointly expecting of two researchs is: intravenous applications cangrelor will reduce the adverse events of PCI early postoperation。
The result of 2009AHA meeting coverage CHAMPIONPLATFORM research and CHAMPIONPCI research。The conclusion that researcher draws according to the research of CHAMPIONPLATFORM and CHAMPIONPCI result of study is: be not better than placebo for its curative effect of intravenous applications cangrelor during the stable angina pectoris of row PCI and ACS corrective surgery。Cangrelor does not reduce PCI interior death in postoperative 48 hours, again stalk and urgent myocardial revascularization rate。But secondary endpoints: full incidence rate cangrelor group dead because of property, thrombus in stents significantly reduces。
Although cangrelor could not enough reduce Primary Endpoint, but the event that its risk doctor just reducing dead and acute stent thrombosis focuses more on, therefore, researcher has carried out CHAMPION-PHOENIX research further。
In on March 10, in, on the 62nd ACC's annual meeting (ACC2013), disclosing CHAMPION-PHOENIX result of study, result of study synchronizes to be published in " New England Journal of Medicine " upper [NEnglJMed2013Mar10]。This research including 11145 example PCI patients in shows, with loading dose chlorine than compared with Gray, cangrelor (cangrelor) can make the incidence rate of death, myocardial infarction (MI), ischemic event and Thrombosis in sten significantly reduce 22% during percutaneous coronary gets involved (PCI), and does not increase bleeding risk。In addition, after cangrelor administration, in the several seconds, namely hematoblastic activation and gathering are suppressed, and its plasma half-life is approximately 10 minutes, in stopping administration latter 60 minutes, hematoblastic functional rehabilitation, therefore this fugitive impart it and starts flexibly and stop rapidly the inhibiting feature of ADP。
In the process preparing cangrelor, its key intermediate has a structure that
Mainly having for this key intermediate and salt Study of synthesis method thereof both at home and abroad: patent CN102089035A, the method needs to use the special equipments such as autoclave in preparation process, higher for producing equipment requirements, and has certain production safety hidden danger。
Therefore, research and development one is easy and simple to handle, product purity is higher, and course of reaction safety is high, is suitable for industrialized production, and the preparation method of cangrelor intermediate with low cost is necessary。
Summary of the invention
The technical problem to be solved in the present invention be to provide a kind of easy and simple to handle, product purity is higher, course of reaction safety is high, is suitable for industrialized production and the preparation method of cangrelor intermediate with low cost。
For solving above-mentioned technical problem, the technical scheme is that a kind of such as formula (I):
The preparation method of shown cangrelor intermediate, its innovative point is in that: described preparation method is with the structural compounds shown in formula (II) for raw material, under solvent and reaction reagent, through specific reaction, reacted product obtains the cangrelor intermediate shown in formula (I) then through purification；Wherein, the concrete structure of formula (II) is:
Described reaction equation is:
Further, described solvent is one or more in series matter, the Isosorbide-5-Nitrae-dioxane series matters such as ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane and series matter, benzene, toluene, it is preferable that ether and one or more in oxolane。
Further, described reaction reagent is one or more in Carbon bisulfide, methanol, DMF, dimethyl sulfoxide, N-methylmorpholine, it is preferable that dimethyl sulfoxide。
Further, the reaction temperature of described specific reaction is-10～200 DEG C, it is preferable that reaction temperature is 140～150 DEG C。
It is an advantage of the current invention that: the preparation method of cangrelor intermediate of the present invention, preparation process need not use the special equipments such as autoclave, relatively low for producing equipment requirements, and then it is easy and simple to handle and improve the security performance of course of reaction, by this preparation method, the product purity prepared is higher and with low cost, is suitable for industrialized production。
Detailed description of the invention
The following examples can make professional and technical personnel more fully understand the present invention, but does not therefore limit the present invention among described scope of embodiments。
In the present invention, without special explanation, percent (%) or part all refer to the percetage by weight relative to compositions or weight portion。
In the present invention, without special explanation, involved each component or its preferred ingredient can be mutually combined and form new technical scheme。
In the present invention, without special explanation, all embodiments mentioned in this article and preferred implementation can be mutually combined and form new technical scheme。
In the present invention, without special explanation, all technical characteristics mentioned in this article and preferred feature can be mutually combined and form new technical scheme。
In the present invention, without contrary explanation, in compositions, the content sum of each component is 100%。
In the present invention, without contrary explanation, in compositions, the number sum of each component can be 100 weight portions。
In the present invention, unless otherwise indicated, numerical range " a-b " represents that the breviary of any real combinings between a to b represents, wherein a and b is real number。Such as numerical range " 0-5 " represents the whole real numbers all listing between " 0-5 " herein, and the breviary that " 0-5 " is these combinations of values represents。
In the present invention, unless otherwise indicated, integer numerical range " a-b " represents that the breviary of the arbitrary integer combination between a to b represents, wherein a and b is integer。Such as integer numerical range " 1-N " represents 1,2 ... N, and wherein N is integer。
In the present invention, unless otherwise indicated, " it combines " represents the multicomponent mixture of described each element, for instance two kinds, three kinds, four kinds and until the multicomponent mixture of maximum possible。
Without particularly pointing out, the term " one " used by this specification refers to " at least one "。
Without particularly pointing out, the benchmark that percent of the present invention (includes percetage by weight) is all the gross weight of described compositions。
" scope " disclosed herein is with the form of lower limit and the upper limit。Can respectively one or more lower limits, and one or more upper limit。Given range is defined by a selected lower limit and a upper limit。Selected lower limit and the upper limit define the border of special scope。All scopes that can be defined by this way comprise and can be combined, and namely any lower limit can form a scope with the combination of any upper limit。Such as, list the scope of 60-120 and 80-110 for special parameter, be interpreted as that the scope of 60-110 and 80-120 also expects。If additionally, the minimum zone value 1 and 2 listed, and if list maximum magnitude value 3,4 and 5, then scope below can all expect: 1-3,1-4,1-5,2-3,2-4 and 2-5。
In this article, except as otherwise noted, the ratio of each component or weight all refer to dry weight。
Embodiment 1
Oxolane (5ml), (II) (27g, 100mmol), methanol (100ml), Carbon bisulfide (100ml) and dimethyl sulfoxide (500ml) being sufficiently stirred at reaction bulb, reactant stirs 12 hours at 140-150 DEG C。After having reacted, decompression is distilled off solvent, washs with ethanol, water and saturated sodium-chloride water solution, dries and obtain product 24g, and yield is 80%。
Spectral data:
1HNMR (500MHz, DMSO) δ 12.15 (s, 1H), 8.35(s, 1H), 6.99 (s, 2H), 6.16 (m, 1H), 4.75-4.40(m, sH), 3.79 (d, 2H), 3.65 (s, 1H), 3.58 (s, 2H)；
MS(ESI):299.07
Embodiment 2
Ether (5ml), (II) (27g, 100mmol), methanol (100ml), Carbon bisulfide (100ml) and dimethyl sulfoxide (500ml) being sufficiently stirred at reaction bulb, reactant stirs 12 hours at 140-150 DEG C。After having reacted, decompression is distilled off solvent, washs with ethanol, water and saturated sodium-chloride water solution, dries and obtain product 23g, and yield is 76.7%。
Spectral data:
1HNMR (500MHz, DMSO) δ 12.15 (s, 1H), 8.35(s, 1H), 6.99 (s, 2H), 6.16 (m, 1H), 4.75-4.40(m, sH), 3.79 (d, 2H), 3.65 (s, 1H), 3.58 (s, 2H)；
MS(ESI):299.07
Embodiment 3
Oxolane and ether (5ml), (II) (27g, 100mmol), methanol (100ml), Carbon bisulfide (100ml) and dimethyl sulfoxide (500ml) being sufficiently stirred at reaction bulb, reactant stirs 12 hours at 140-150 DEG C。After having reacted, decompression is distilled off solvent, washs with ethanol, water and saturated sodium-chloride water solution, dries and obtain product 23.5g, and yield is 78.3%。
Spectral data:
1HNMR (500MHz, DMSO) δ 12.15 (s, 1H), 8.35(s, 1H), 6.99 (s, 2H), 6.16 (m, 1H), 4.75-4.40(m, sH), 3.79 (d, 2H), 3.65 (s, 1H), 3.58 (s, 2H)；
MS(ESI):299.07
The ultimate principle of the present invention and principal character and advantages of the present invention have more than been shown and described。Skilled person will appreciate that of the industry; the present invention is not restricted to the described embodiments; described in above-described embodiment and description is that principles of the invention is described; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements both fall within the claimed scope of the invention。Claimed scope is defined by appending claims and equivalent thereof。
Claims (4)
1. one kind such as formula (I):
The preparation method of shown cangrelor intermediate, it is characterized in that: described preparation method is with the structural compounds shown in formula (II) for raw material, under solvent and reaction reagent, through specific reaction, reacted product obtains the cangrelor intermediate shown in formula (I) then through purification；Wherein, the concrete structure of formula (II) is:
Described reaction equation is:
。
2. the preparation method of Gray Lip river according to claim 1 intermediate, it is characterized in that: described solvent be the series matters such as ether, diisopropyl ether, methyl tertiary butyl ether(MTBE), oxolane and series matter, benzene, toluene, 1, one or more in 4-dioxane series matter, it is preferable that ether and one or more in oxolane。
3. the preparation method of Gray Lip river according to claim 1 intermediate, it is characterised in that: described reaction reagent is one or more in Carbon bisulfide, methanol, DMF, dimethyl sulfoxide, N-methylmorpholine, it is preferable that dimethyl sulfoxide。
4. the preparation method of Gray Lip river according to claim 1 intermediate, it is characterised in that: the reaction temperature of described specific reaction is-10～200 DEG C, it is preferable that reaction temperature is 140～150 DEG C。
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| CN201610253038.9A CN105693800A (en) | 2016-04-22 | 2016-04-22 | Preparation method of Cangrelor intermediate |
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| CN201610253038.9A CN105693800A (en) | 2016-04-22 | 2016-04-22 | Preparation method of Cangrelor intermediate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724181A (en) * | 2020-12-30 | 2021-04-30 | 盐城锦明药业有限公司 | Method for preparing Cangrelor intermediate adenosine-2-thioketone |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5132590A (en) * | 1974-09-13 | 1976-03-19 | Kojin Kk | 22 chioadenoshin oyobi 22 chikanchioadenoshinrui no seizohoho |
| US3989682A (en) * | 1974-07-12 | 1976-11-02 | Kohjin Co., Ltd. | Process for preparing 2-thioadenosine |
| CN105273025A (en) * | 2014-07-22 | 2016-01-27 | 上海医药工业研究院 | Intermediate for preparing cangrelor and preparation method and application thereof |
-
2016
- 2016-04-22 CN CN201610253038.9A patent/CN105693800A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3989682A (en) * | 1974-07-12 | 1976-11-02 | Kohjin Co., Ltd. | Process for preparing 2-thioadenosine |
| JPS5132590A (en) * | 1974-09-13 | 1976-03-19 | Kojin Kk | 22 chioadenoshin oyobi 22 chikanchioadenoshinrui no seizohoho |
| CN105273025A (en) * | 2014-07-22 | 2016-01-27 | 上海医药工业研究院 | Intermediate for preparing cangrelor and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| J. ZIMMET，等: ""SYNTHESIS AND BIOLOGICAL ACTIVITY OF NOVEL 2-THIO DERIVATIVES OF ATP"", 《NUCLEOSIDES & NUCLEOTIDES》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112724181A (en) * | 2020-12-30 | 2021-04-30 | 盐城锦明药业有限公司 | Method for preparing Cangrelor intermediate adenosine-2-thioketone |
| CN112724181B (en) * | 2020-12-30 | 2022-09-13 | 盐城师范学院 | Method for preparing Cangrelor intermediate adenosine-2-thioketone |
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Application publication date: 20160622 |