CN105273025B - A kind of intermediate and its preparation method and application preparing cangrelor - Google Patents
A kind of intermediate and its preparation method and application preparing cangrelor Download PDFInfo
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Abstract
The invention belongs to cangrelor preparation method technical fields.The invention discloses new intermediate compounds 4 for preparing cangrelor and preparation method thereof.The advantages that applicant of the present invention is by replacement N-protected base, using the weaker formoxyl of activity as N protecting group, smoothly obtains a kind of intermediate 4 of new N- formoxyl protection, which has purity is high, and stability is good, and preparation method is easily operated.Solve in the prior art that yield is low, product is difficult to the difficulty of purifies and separates.
Description
Technical field
The present invention relates to cangrelor preparation method technical fields.
Background technique
Cangrelor, English name: cangrelor, chemical name: N- [2- (methyl mercapto) ethyl] -2- [(3,3,3- trifluoropropyls
Base) thio] -5'-AMP, single acid anhydride with dichloromethylene diphosphonic acid, tetrasodium salt, chemical structural formula:
Pharmaceuticals, cangrelor system The Medicines Company exploitation, is currently under the clinical trial of III phase, belongs to
In platelet ADP (P2Y12) receptor antagonist class antiplatelet drug.
About the synthesis of cangrelor, in patent CN1042430C and paper J.Med.Chem.1999,42,213-220
In have and specially state, all these documents have used N- acetyl group -2- [(3,3,3- trifluoro propyl) is thio] adenosine-bar none
2', 3', 5'- triethyl (6 compound of following formula) are as a key intermediate in synthetic route.With J.Med.Chem.1999,
For 42,213-220,2- [(3,3,3- trifluoro propyl) is thio] adenosine (1) is starting material, generates tetrem with acetic anhydride
Compound N-acetyl -2- [(3,3,3- trifluoro propyl) is thio] adenosine -2', 3', 5'- triethyl (6) of acyl protection, then changes
6 nucleo philic substitution reaction of object is closed, basic hydrolysis deacetylation obtains cangrelor key intermediate (5), then bank is made through phosphorylated
Gray Lip river, as shown in formula 1-2.
Analyze the conjunction of existing N- acetyl group -2- [(3,3,3- trifluoro propyl) is thio] adenosine -2', 3', 5'- triethyl (6)
At route it is found that in practical acylation process, in 2- [(3,3,3- trifluoro propyl) is thio] adenosine (1) and acetic anhydride, and
It cannot obtain the target product of four pure acetylations.Tracing it to its cause is 2- [(3,3,3- trifluoro propyl) is thio] 6 nitrogen originals of adenosine
The activity of son is stronger, is also easy to produce the by-product of diacetylation on N in acetylation, is shown below.The production of the by-product
It coins into purifying products difficulty, gradually bring into subsequent product.
Summary of the invention
The object of the invention is to overcome the above problem of the existing technology, a kind of new cangrelor for preparing is provided
Intermediate.Using the new intermediate, simply high yield cangrelor can be obtained.
It is a further object to provide the preparation method and application of the new intermediate.
In order to achieve the above object, technical scheme is as follows:
The compound 4 of following formula:
Compound 4, its chemical name is N- formoxyl-N- [2- (methyl mercapto) ethyl] -2- [(3,3,3- trifluoro propyl) sulphur
Generation] adenosine -2', 3', 5'- triacetyl.
The preparation method of 4 compound of formula, this method are that compound 3 is dissolved in reaction dissolvent, and 2- is added under alkaline condition
Chloroethene methyl sulfide reacts to obtain
The preparation method of above-mentioned 4 compound of formula, the alkaline condition can be inorganic base potassium carbonate, sodium carbonate etc., or
Organic bases triethylamine, pyridine etc.；It is preferred that potassium carbonate or sodium carbonate.
Further, 3 compound of formula is that formic acid is added after acetic anhydride to be down to room temperature, and the reaction of compound 2 is added and obtains
The preparation of above-mentioned 3 compound of formula, preferred condition are that formic acid is added after acetic anhydride in 40-60 DEG C of reaction 20-
Room temperature is down to after 40min.Reaction temperature after compound 2 is added is generally at 60-100 DEG C.Compound 2 and formic acid feed intake mole
Than for 1:4-1:50, the molar ratio of compound 2 and acetic anhydride is 1:4-:1:10.
Further, 2 compound of formula is that 2- [(3,3,3- trifluoro propyl) is thio] adenosine is dissolved in acetic anhydride addition to tie up
Sour agent reacts to obtain:
The preparation method of above-mentioned 2 compound of formula, temperature is -15 DEG C -40 DEG C when reaction, preferably at -5 DEG C -20 DEG C.Described
Acid binding agent can be sodium acetate, pyridine, triethylamine etc., preferably pyridine.The molar ratio of compound 1 and acetic anhydride is 1:5-1:
50。
4 compound of formula is used to prepare cangrelor and other known intermediate, yield and purity is all bigger than the prior art has
It improves.
It is as follows that 4 compound of formula is used to prepare the step of cangrelor and other known intermediate:
1) compound 4 is hydrolyzed under alkaline condition and obtains compound 5
The method that midbody compound 5 prepares cangrelor can refer to the prior art.
Beneficial effects of the present invention: the main reason for prior art products obtained therefrom purity is not high is two on the N of adenosine
Hydrogen atom has quite activity, is easy to replaced acetyl group, and two hydrogen atoms are without selectivity, easy while upper two guarantors
Base is protected, causes yield low, product is difficult to the difficulty of purifies and separates.Applicant of the present invention is by replacement N-protected base, using work
Property weaker formoxyl as N protecting group, smoothly obtain a kind of intermediate of new N- formoxyl protection, which has pure
The advantages that degree is high, and stability is good, and preparation method is easily operated.
Specific embodiment
Below with reference to embodiment, present invention is further described in detail, but does not therefore limit the present invention to described
Among scope of embodiments.
Experimental material and reagent involved in the following contents are then commercially available product if not otherwise specified.From existing raw material to
The reaction route that midbody compound 5 is made is as follows:
The synthesis of embodiment 1-4:2- [(3,3,3- trifluoro propyl) is thio] adenosine -2', 3', 5'- triethyl (2)
By 2- [(3,3,3- trifluoro propyl) is thio] adenosine (10.0g, 25.3mmol) be dissolved in pyridine (20ml, 253mmol,
In 10eq), acetic anhydride (35ml, 5eq) is added dropwise under ice bath, -5 DEG C of reaction 3h add 100ml elutriation to go out white solid, and stirring 1h takes out
Filter to obtain white solid 11.35g, yield 86%.ESI-MS (m/z): 522.13 [M+H]+, 544.11 [M+Na]+, 560.09 [M+K
]+；1H NMRδ(CDCl3) 7.87 (1H, s, H-8), 6.14 (1H, d, H-1'), 5.82 (1H, t, H-2'), 5.67 (2H, s,
NH2), 5.45 (1H, m, H-3'), 4.41 (3H, m, H-4', 5'), 3.29 (2H, m, SCH2), 2.63 (2H, m, CF3CH2), 2.13
(3H, s, CH3CO), 2.12 (3H, s, CH3CO), 2.07 (3H, s, CH3CO)。
By 2- [(3,3,3- trifluoro propyl) is thio] adenosine (5.0g, 12.65mmol) be dissolved in acetic anhydride (60ml,
632.34mmol, 50eq) in be down to -15 DEG C, be added triethylamine (3.84g, 3eq), react 7h, add 50ml elutriation to go out white solid
Body, stirring 1h filter to obtain white solid 3.94g, yield 60%.
By 2- [(3,3,3- trifluoro propyl) is thio] adenosine (10.0g, 25.3mmol) be dissolved in pyridine (26ml, 324mmol,
In 13eq), acetic anhydride (40ml, 426mmol, 17eq) is added dropwise under ice bath, 10 DEG C of reaction 3h add 100ml elutriation to go out white solid,
Stirring 1h filters to obtain white solid 11.35g, yield 86%.
By 2- [(3,3,3- trifluoro propyl) is thio] adenosine (5.0g, 12.65mmol) and sodium acetate (0.62g,
7.59mmol, 0.6eq) 40 DEG C of reaction 5h in acetic anhydride (6ml, 63.2mmol, 5eq) are dissolved in, add 10ml elutriation to go out white solid,
Stirring 1h filters to obtain white solid 4.48g, yield 68%.
The conjunction of embodiment 5-8N- formoxyl -2- [(3,3,3- trifluoro propyl) is thio] adenosine -2', 3', 5'- triacetyl (3)
At
It will be stirred at 50 DEG C of formic acid (13ml, 345mmol, 18eq) addition acetic anhydride (27ml, 288mmol, 15eq) under low temperature
30min is mixed, room temperature is down to, is added compound 2 (10.0g, 19.2mmol), 70 DEG C of reaction 3.5h.Add water 65ml that white is precipitated solid
Body, 20 DEG C or so stirring 2h filter to obtain compound (3) (9.86g, yield 94.0%).ESI-MS (m/z): 572.15 [M+Na]+；
1H NMRδ(CDCl3) 9.83 (2H, s, NH+CHO), 8.40 (1H, s, H-8), 6.21 (1H, d, H-1'), 5.85 (1H, t, H-
2'), 5.56 (1H, t, H-3'), 4.40 (3H, 4-H'+5-2H'), 3.32 (2H, SCH2), 2.64 (2H, CF3-CH2), 2.15-
2.07 (6H, CH3CO)。
Acetic anhydride (7.25ml, 76.7mmol, 10eq) is added in formic acid (14.47ml, 383.5mmol, 50eq) under low temperature
30min is stirred at 50 DEG C, is down to 25 DEG C, is added compound 2 (4.0g, 7.67mmol), 60 DEG C of reaction 10h.Water 65ml is added to be precipitated
White solid, 20 DEG C or so stirring 2h filter to obtain compound (3) (3.50g, yield 83%).
It will be stirred at 50 DEG C of formic acid (13ml, 345mmol, 18eq) addition acetic anhydride (27ml, 288mmol, 15eq) under low temperature
30min is mixed, room temperature is down to, is added compound 2 (10.0g, 19.2mmol), 80 DEG C of reaction 3.5h.Add water 65ml that white is precipitated solid
Body, 20 DEG C or so stirring 2h filter to obtain compound (3) (9.86g, yield 94.0%)
By 50 DEG C of formic acid (1.74ml, 46.0mmol, 4eq) addition acetic anhydride (4.35ml, 46.0mmol, 4eq) under low temperature
Lower stirring 30min is down to 25 DEG C, is added compound 2 (6.0g, 11.5mmol), 100 DEG C of reaction 2h.Add water 65ml that white is precipitated
Solid, 20 DEG C or so stirring 2h filter to obtain compound (3) (5.06g, yield 80%)
Embodiment 9-12:N- formoxyl-N- [2- (methyl mercapto) ethyl] -2- [(3,3,3- trifluoro propyl) is thio] adenosine -
The synthesis of 2', 3', 5'- triacetyl (4)
Compound 3 (8.0g, 14.6mmol) is dissolved in 80mlDMF, is added potassium carbonate (4.02g, 2eq), 60 DEG C anti-
1h is answered, 2- chloroethene methyl sulfide (4.35ml, 3eq) 60 DEG C of reaction 2h are added, obtain dark syrup object 8.58g, yield 94%.
TLC (methylene chloride: methanol=20:1) Rf=0.9.
Compound 3 (5.0g, 9.1mmol) is dissolved in 50mlDMF, is added triethylamine (1.3ml, 1eq), 60 DEG C of reactions
1h is added 2- chloroethene methyl sulfide (1.81ml, 2eq) 25 DEG C of reaction 15h, obtains dark syrup object 3.42g, yield 60%.
Compound 3 (4.0g, 7.3mmol) is dissolved in 40mlDMF, is added sodium carbonate (1.54g, 2eq), 60 DEG C of reactions
1h is added 2- chloroethene methyl sulfide (2.2ml, 3eq) 60 DEG C of reaction 2h, obtains dark syrup object 4.34g, yield 95%.
Compound 3 (4.0g, 7.3mmol) is dissolved in 40mlDMF, is added sodium acetate (1.19g, 2eq), 60 DEG C of reactions
1h is added 2- chloroethene methyl sulfide (2.2ml, 3eq) 100 DEG C of reaction 1h, obtains dark syrup object 3.50g, yield 80%.
The synthesis of embodiment 13:N- [2- (methyl mercapto) ethyl] -2- [(3,3,3- trifluoro propyl) is thio] adenosine (5)
Compound 4 (2.57g, 4.1mmol) is dissolved in the methanol (80ml) of sodium hydroxide (2.14g, 53.6mmol, 13eq)
In solution, flow back 1h, and decompression evaporates methanol, adds water, and white solid 1.72g, yield 89% is precipitated.
ESI-MS (m/z): 624 [M+H]+, 646 [M+Na ,]+；1H NMR(DMSO-d6, 400MHz) and δ: 8.25 (1H, s, H-
8), 8.02 (1H, s, NH), 5.82 (1H, d), 5.36 (1H, s, OH), 5.11 (1H, s, OH), 5.00 (1H, s, OH), 4.56
(1H), 4.13 (2H), 3.92 (1H, m), 3.63, (4H), 3.27 (2H), 2.72 (4H), 2.06 (3H, s, SCH3)。
Claims (14)
1. the compound 4 of following formula:
2. the preparation method of 4 compound of formula, comprising: compound 3 is dissolved in reaction dissolvent, in the presence of a base, 2- chloroethene is added
Methyl sulfide reacts to obtain
3. preparation method as claimed in claim 2, it is characterised in that: the alkali used be potassium carbonate, sodium carbonate or triethylamine,
Pyridine.
4. preparation method as claimed in claim 3, it is characterised in that: the alkali used is potassium carbonate or sodium carbonate.
5. preparation method as claimed in claim 2, it is characterised in that: formic acid is down to room temperature after acetic anhydride is added, and chemical combination is added
Object 2, reaction obtain 3 compound of formula,
6. preparation method as claimed in claim 5, it is characterised in that: after acetic anhydride is added in formic acid, in 40-60 DEG C of reaction 20-
It is down to room temperature after 40min, compound 2 is added, reaction obtains 3 compound of formula.
7. preparation method as claimed in claim 5, it is characterised in that: the molar ratio of compound 2 and formic acid is 1:4-1:50, is changed
The molar ratio for closing object 2 and acetic anhydride is 1:4-1:10.
8. preparation method as claimed in claim 5, it is characterised in that: under conditions of reaction temperature is -15 DEG C -40 DEG C, 2-
[(3,3,3- trifluoro propyl) is thio] adenosine is dissolved in acetic anhydride, and in the presence of acid binding agent, and reaction obtains 2 compound of formula,
9. preparation method as claimed in claim 8, it is characterised in that: at -5 DEG C -20 DEG C of reaction temperature, formula 2 is prepared
Compound.
10. preparation method as claimed in claim 8, it is characterised in that: the acid binding agent is sodium acetate, pyridine or three second
Amine.
11. preparation method as claimed in claim 10, it is characterised in that: the acid binding agent is pyridine.
12. preparation method as claimed in claim 8, it is characterised in that: the molar ratio of compound 1 and acetic anhydride is 1:5-1:
50。
13. 4 compound of formula is preparing the application in cangrelor
14. application as claimed in claim 13 comprising:
1) compound 4 is hydrolyzed under alkaline condition and obtains compound 5
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| CN105693800A (en) * | 2016-04-22 | 2016-06-22 | 南通宏慈药业有限公司 | Preparation method of Cangrelor intermediate |
| CN105949258B (en) * | 2016-05-06 | 2019-05-31 | 浙江永宁药业股份有限公司 | A kind of synthetic method of cangrelor intermediate |
| CN106397516B (en) * | 2016-08-30 | 2019-09-27 | 北京沣瑞医药科技有限公司 | Cangrelor intermediate and its preparation method and application |
| CN107973798B (en) * | 2016-10-25 | 2020-04-24 | 上海医药工业研究院 | 2- [ (3,3, 3-trifluoropropyl) thio ] -6-amino-9H-purine and its preparation |
| CN107462648B (en) * | 2017-08-21 | 2019-09-27 | 盐城锦明药业有限公司 | A kind of high-efficiency liquid chromatography method for detecting of Cangrelor intermediate adenosine -2- thioketones |
| CN109912673B (en) * | 2017-12-12 | 2022-01-25 | 亚宝药业集团股份有限公司 | Cangrelor intermediate and preparation method thereof |
| CN109912674A (en) * | 2017-12-12 | 2019-06-21 | 亚宝药业集团股份有限公司 | A kind of preparation method of cangrelor tetrasodium salt |
| JP7381913B2 (en) * | 2021-10-13 | 2023-11-16 | ダイキン工業株式会社 | Pest control composition |
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| DK155292D0 (en) * | 1992-12-23 | 1992-12-23 | Novo Nordisk As | CHEMICAL COMPOUNDS, THEIR PREPARATION AND USE |
| JP6577165B2 (en) * | 2011-01-26 | 2019-09-18 | 北京康倍得医▲藥▼技▲術▼▲開▼▲發▼有限公司 | Ribofuranosylpurine compound, process for its preparation and use thereof |
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| CN1042430C (en) * | 1993-02-10 | 1999-03-10 | 英国阿斯特拉药品有限公司 | N-alkyl-2-substituted ATP analogues |
| CN1466591A (en) * | 2000-08-30 | 2004-01-07 | - | Nucleoside derivatives |
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