CN105949258A - Synthesis method of cangrelor intermediate - Google Patents
Synthesis method of cangrelor intermediate Download PDFInfo
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- CN105949258A CN105949258A CN201610301468.3A CN201610301468A CN105949258A CN 105949258 A CN105949258 A CN 105949258A CN 201610301468 A CN201610301468 A CN 201610301468A CN 105949258 A CN105949258 A CN 105949258A
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- 0 CC(C(*1c2nc(SCCC(F)(F)F)nc(NCCSC)c2N=C1)O[C@@]1CO)[C@]1O Chemical compound CC(C(*1c2nc(SCCC(F)(F)F)nc(NCCSC)c2N=C1)O[C@@]1CO)[C@]1O 0.000 description 3
- XBOQUWBBQQPQTC-AGZNMWJWSA-N C[C@H](C(C1N=O)OC)OC1N1C2=NC(C)NC(NC)=C2N=C1 Chemical compound C[C@H](C(C1N=O)OC)OC1N1C2=NC(C)NC(NC)=C2N=C1 XBOQUWBBQQPQTC-AGZNMWJWSA-N 0.000 description 1
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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
Abstract
Belonging to the field of chemical synthesis of drugs, the invention in particular relates to a synthesis method of a compound cangrelor intermediate shown as formula (6). The invention provides a new synthesis method of the cangrelor intermediate (compound 6). The method includes: taking thioadenosine as the raw material, firstly carrying out reaction with a diazotization reagent and a halogenated reagent, then carrying out reaction with 2-(methylthio)ethylamine, and finally conducting hydrolysis to obtain a compound 6. The method has the advantages of cheap raw materials, efficient reaction, safety and easy operation, and is conducive to industrial production. (formula 6).
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis field, be specifically related to the synthetic method of a kind of cangrelor intermediate.
Background technology
Platelet plays an important role in thrombosis, and adenosine diphosphate (ADP) (ADP) is present in platelet cell
In high density granular, being released when platelet generation aggregation, ADP passes through the adp receptor on platelet membrane to platelet
Shape and biological behaviour produce impact, further speed up hematoblastic coacervation process.P2Y12 receptor antagonist can suppress
Platelet aggregation and do not affect ADP mediation vascular reaction, P2Y12 receptor antagonist is divided into thiophene pyridines by its chemical constitution
With non-thiophene pyridines, thiophene pyridines (clopidogrel and prasugrel) and non-thiophene pyridines are (such as promise Gray, Ticagrelor
And cangrelor).
Containing triphosphoric acid side chain in the structure of cangrelor, in vivo without metabolism just can with P2Y12 receptor directly in conjunction with, press down rapidly
Make hematoblastic gathering.And half-life in vivo is short, only 2.6min, plasma clearance is 50L/h.Cangrelor becomes
A kind of preferable anti-platelet aggregation medicine used for intravenous injection.II phase clinical studies show, the anti-platelet aggregation of cangrelor is made
With being better than clopidogrel, and there is good safety.The additionally anti-platelet aggregation effect of cangrelor and glycoprotein p II b/
III a receptor antagonist is suitable, can preferably control the bleeding time.Therefore, cangrelor becomes a kind of preferable used for intravenous injection anti-
Platelet aggregation medicine.
Cangrelor is researched and developed by AstraZeneca, obtains FDA approval listing on June 22nd, 2015, and its clinical indication is little as anti-blood
Plate medicinal application is treated with acute coronary syndrome in percutaneous coronary intervention (pci), and its structural formula is as follows:
In existing document, the synthesis about cangrelor relates to a series of compound, and compound shown in its Chinese style (6) is synthesis bank lattice
The key intermediate of Lei Luo, its chemical name is: (2R, 3S, 4R, 5R)-2-hydroxymethyl-5-(6-((2-methylthioethyl)
Amino)-2-(3,3,3-trifluoro propyl sulfur generation)-9H-purine-9-base) oxolane-3,4-glycol, structural formula is:
Document J.Med.Chem.1999, reports the synthesis about compound (6) in 42,213-220, its route is as follows:
This route with sulfydryl adenosine as raw material, through replacing, be esterified, replacing, hydrolysis synthesis compound (6), in reaction
The 2-chloroethyl Dimethyl sulfide used is a kind of flammable liquid, has strong impulse abnormal smells from the patient, and expensive, raw material is difficult to obtain
, and environment is had harm, 2-chloroethyl Dimethyl sulfide is difficult to carry out with the reaction of amino simultaneously, and yield is low, the most unfavorable
In environment maintenance and industrialized production.
Additionally, also disclose that the synthesis about compound (6) in patent WO2012100654, this route, with guanosine as raw material, divides
Do not react conjunction with phosphorus oxychloride, two (trifluoro propyl) disulfide (compound (VII)), 2-(methyl mercapto) ethamine, sodium acetate
Becoming compound (6), concrete synthetic route is as follows:
The utilization rate of the compound (VII) used in above-mentioned route only has 50%, and 6 times that its inventory is compound (III),
I.e. compound (VII) consumption is big and utilization rate is low, due to prepare the raw material trifluoro iodopropane of compound (VII) be one very
Expensive reagent, in the case of the big utilization rate of compound (VII) consumption is low, considerably increases reaction cost, is unfavorable for industry
Metaplasia is produced；In addition, the phosphorus oxychloride used in course of reaction has severe toxicity, operates dangerous.
Summary of the invention
In order to overcome defect present in prior art, the present invention provides a kind of safe efficient, low cost, easy-operating bank lattice
The synthetic method of thunder Lip river intermediate.
It is an object of the invention to provide the synthetic method of compound shown in a kind of formula (6), described method includes:
1) compound (4) is synthesized compound (5) with diazo reagent and halogenating agent；
Wherein X is halogen, and R is alkyl-carbonyl, preferably methyl carbonyl, ethylcarbonyl group, propyl group carbonyl, more preferably ethylcarbonyl group.
Described diazo reagent is the conventional diazo reagent such as nitrites or nitrite, preferably nitrites, more preferably nitrous
Isoamyl valerate or nitrite tert-butyl.
Described halogenating agent can be copper halide or halogenated alkane etc., preferably copper bromide, copper chloride, more preferably copper bromide.
The temperature of described one pot reaction is less than or equal to 50 DEG C, preferably 30-50 DEG C.
Described reaction is carried out in conventional organic solvent (such as ethanol, acetone etc.).
2) compound (5) and 2-(methyl mercapto) ethamine are synthesized compound (5-1)；
Wherein X is halogen, and R is alkyl-carbonyl, preferably methyl carbonyl, ethylcarbonyl group, propyl group carbonyl, more preferably ethylcarbonyl group.
Described reaction is carried out in the basic conditions, and described alkali can be that triethylamine, N-methylmorpholine, sodium acetate, N, N-bis-are different
The weak base, preferably DIPEA (DIEA) such as propylethylamine (DIEA).
Carry out at conventional organic solvent under described reaction room temperature.
3) compound (5-1) is through hydrolysis synthesis compound (6), and reaction scheme is as follows:
Wherein R is alkyl-carbonyl, preferably methyl carbonyl, ethylcarbonyl group, propyl group carbonyl, more preferably ethylcarbonyl group.
The popular response that described hydrolysis is well known to those skilled in the art, such as, carried out under highly basic or strong acid condition.
Further, the synthetic method of above-claimed cpd (6) also includes that the synthesis of compound (4), described synthesis include chemical combination
Thing (2) is carried out by replacing and being esterified two-step reaction:
Wherein R is alkyl-carbonyl, preferably methyl carbonyl, ethylcarbonyl group, propyl group carbonyl, more preferably ethylcarbonyl group.
Described substitution reaction is carried out in the highly basic such as alkali metal hydroxide；Described esterification is carried out under the conditions of weak base, described
Weak base includes organic amine compound, sodium acetate, alkali carbonate, alkali metal hydrogencarbonate etc., preferably triethylamine, carbonic acid
Sodium, sodium bicarbonate, more preferably triethylamine；
Described esterification is carried out in the presence of DMAP (DMAP).
Described esterification is at room temperature carried out, such as, carry out at 0-30 DEG C, preferably carries out at 15-30 DEG C, more preferably exists
Carry out at 20-25 DEG C；Reaction time of esterification is preferably 0.5-2 hour, more preferably 0.5 hour.
Further, above-claimed cpd (2) can by commercially available acquisition or list of references Chem.Pharm.Bull., 25 (8),
1959-1969, (1977) prepare.
Further, above-claimed cpd (6-2) can be prepared by commercially available or patent WO2013131465.
In the route that the present invention provides, trifluoro iodopropane consumption little (conventional amount used), utilization rate improve, and greatly reduce reaction
Cost；Additionally, the present invention is by by the amino part halogen substiuted of compound (4), then react with 2-(methyl mercapto) ethamine
Synthesis compound (5-1), thus avoid using 2-chloroethyl Dimethyl sulfide in course of reaction, 2-(methyl mercapto) ethamine is compared
Be easy to get in 2-chloroethyl Dimethyl sulfide raw material, low price, and the reaction of 2-(methyl mercapto) ethamine and halogen is more easy to carry out,
Inherently improve reaction yield and reduce production cost, being conducive to carrying out industrialized production.The present invention provides a kind of new
The synthetic method of cangrelor intermediate (compound 6), with sulfydryl adenosine as raw material, first with diazo reagent and halogenating agent
Reaction, then react with 2-(methyl mercapto) ethamine, finally hydrolysis obtains compound 6；The cost of material that the method uses is cheap and anti-
Should efficiently, safety easily operation, be conducive to carrying out industrialized production.
Detailed description of the invention
Below in conjunction with embodiment, the invention will be further described, but the protection content of the present invention is not limited only to these embodiments.
In the following example, method therefor is if no special instructions, is conventional method.Raw material of the present invention and reagent can
Obtained by commercially available purchase.
Embodiment 1:
In 2L there-necked flask, add compound 2 (50g, 0.167mol), 0.5mol/L NaOH solution (840mL), stir 10min.
Add trifluoro iodopropane (45g, 0.2mol), reaction 4-5 hour is stirred at room temperature.Adding the extraction of 500mL ethyl acetate, organic facies is used
Anhydrous sodium sulfate is dried, and filters, and filtrate decompression is evaporated to obtain yellow solid 55.5g, and productivity is 84%.
Embodiment 2:
Compound 3 (25.3g, 0.064mol), 100mL acetonitrile, 26g triethylamine, 0.6g is added in the there-necked flask of 500mL
DMAP, is slowly added dropwise 23g acetic anhydride under stirring, after adding, control temperature and react 0.5h in the range of 20-25 DEG C.Add
25mL methanol, stirs 30min, and decompression evaporates solvent, adds the making beating of 100mL isopropanol, filters, obtain the white of compound 4a
Color solid 31.0g, productivity is 93%.
The nuclear magnetic data of compound 4a is:1H NMR(400MHz,DMSO)δ8.24(s,1H),7.53(s,2H),6.17(d,J
=5.1Hz, 1H), 6.04 5.97 (m, 1H), 5.54 (t, J=5.5Hz, 1H), 4.42 4.34 (m, 2H), 4.24 (td, J=6.9,
2.8Hz,1H),3.29–3.24(m,2H),2.79–2.64(m,2H),2.11(s,3H),2.04(s,3H),2.00(s,3H)。
Embodiment 3:
Preparing compound 4a according to the method for embodiment 2, the inventory of compound 3, based on 0.064mol, is separately added into different alkali,
Adjust the scope of temperature, and monitor response situation in real time；In embodiment 2, triethylamine is as alkali, and temperature is 20-25 DEG C of conduct comparison,
Result is as shown in the table: when using highly basic or reaction temperature too high, due to the generation of by-product 4a ', cause target product
Yield reduces；When the temperature is too low, the response time extends, and reaction is difficult to completely.
Embodiment 4:
Adding compound 4a (21g, 0.04mol), 50mL THF in the there-necked flask of 250mL, stirring lower addition nitrous acid is different
Pentyl ester (23g, 0.2mol), copper bromide (13.4g, 0.06mol), control temperature in the range of 30-50 DEG C, react two hours,
Evaporated under reduced pressure, adds 200mL ethyl acetate and 300mLNaHCO3Solution, extraction, the washing of 80mL saturated NaCl solution has
Machine layer, evaporated under reduced pressure, obtain crude product, crude product silicagel column separates, and obtains white solid (compound 5a) 17.1g, and productivity is
73%.The crude product of above-mentioned gained also can be directly used in the next step without isolation.
The nuclear magnetic data of compound 5a is:1H NMR (400MHz, CDCl3) δ 8.20 (s, 1H), 6.19 (d, J=5.0Hz, 1H),
5.78 (t, J=5.2Hz, 1H), 5.50 (t, J=5.2Hz, 1H), 4.47 (dd, J=8.3,3.6Hz, 1H), 4.39 (t, J=3.2Hz,
2H), 3.43 3.25 (m, 2H), 2.63 (ddd, J=9.3,8.6,4.0Hz, 2H), 2.14 (s, 3H), 2.13 (s, 3H), 2.07 (s,
3H)。
Embodiment 5:
Adding compound 4a (21g, 0.04mol), 50mL THF in the there-necked flask of 250mL, stirring lower addition nitrous acid is different
Pentyl ester (23g, 0.2mol), copper bromide (13.4g, 0.06mol), it is heated to 60 DEG C and reacts two hours, evaporated under reduced pressure, add
200mL ethyl acetate and 300mLNaHCO3Solution, extraction, 80mL saturated NaCl solution washing organic layer, evaporated under reduced pressure,
Obtaining crude product, crude product silicagel column separates, and obtains white solid (compound 5a) 11.4g, and productivity is 49%.
Embodiment 6:
Compound 4a (15.6g, 0.03mol) is dissolved in the mixed solvent of 50mL acetic acid and 60mL water, is heated to 65 DEG C,
It is slowly added to sodium nitrite (4.14g, 0.06mol), stirred overnight at room temperature, obtains yellow solid, water and washing with alcohol yellow solid.
Yellow solid is dissolved in DMF, adds copper bromide, be heated to 65 DEG C, react 8h, after completion of the reaction, remove solvent, use DCM
Washing twice, obtain white solid 7.3g, productivity is 42%.
Embodiment 7:
Compound 4a (21g, 0.04mol), 60mLCH is added in the reaction bulb of 250mL2Br2, it is stirred at room temperature, adds Asia
Isoamyl nitrate (23g, 0.2mol), is heated to 45 DEG C of reaction 4h.Reactant liquor is poured in single port bottle, evaporated under reduced pressure, obtain
Crude product, crude product silicagel column separates, and obtains white solid 12.6g, and productivity is 54%.
Embodiment 8:
Adding compound 4a (21g, 0.04mol), 50mL THF in the there-necked flask of 250mL, stirring lower addition nitrous acid is different
Pentyl ester (23g, 0.2mol), copper chloride (10.2g, 0.06mol), control temperature in the range of 30-50 DEG C, react two hours,
Evaporated under reduced pressure, adds 200mL ethyl acetate and 300mL NaHCO3Solution, extraction, the saturated NaCl solution of 80mL is washed
Organic layer, evaporated under reduced pressure, obtain crude product, crude product silicagel column separates, and obtains white solid 14.9g, and productivity is 69%.
Embodiment 9:
In 50L reactor add compound 4a (2.1kg, 4mol), 5L THF, add under stirring amyl nitrite (2.3kg,
20mol), copper bromide (1.34kg, 6mol), control temperature in the range of 30-50 DEG C, is reacted two hours, evaporated under reduced pressure, is fallen
Enter 10L ethyl acetate and 15L NaHCO3Solution, extraction, 8L saturated NaCl solution washing organic layer, evaporated under reduced pressure,
To crude product, crude product silicagel column separates, and obtains white solid 1.66kg, and productivity is 71%.Above-mentioned gained crude product also can without isolation,
It is directly used in the next step.
Embodiment 10:
Adding compound 5a (25g, 0.043mol) in the there-necked flask of 500mL, 100mL dichloromethane dissolves, is separately added into
Compound 6-2 (4.6g, 0.05mol), DIEA (11g, 0.086mol), stirred overnight at room temperature, reactant liquor is washed, and reduces pressure and steams
Dry, obtain crude product (the next step can be directly used in without isolation), crude product silicagel column separates, and obtains 18.4g white solid and (changes
Compound 5a-1), productivity is 72%.
Embodiment 11:
Adding compound 5b (23g, 0.043mol) in the there-necked flask of 500mL, 100mL dichloromethane dissolves, is separately added into
Compound 6-2 (4.6g, 0.05mol), DIEA (11g, 0.086mol), overnight, TLC monitors room temperature reaction, and reaction is completely
After, separating with silicagel column, obtain 17.1g white solid (compound 5a-1), productivity is 67%.
Embodiment 12:
In the there-necked flask of 250mL, add compound 5a-1 (20g, 0.033mol), 15mL methanol, be cooled to 5 DEG C, by 15mL
Sodium hydroxide solution (the wherein 2g Han sodium hydroxide) is slowly added dropwise to reactant liquor, filters, obtain compound 6 after stirring 15min
Light yellow solid 13.9g, productivity is 90%.
The nuclear magnetic data of compound 6 is:1H NMR (400MHz, DMSO) δ 8.27 (s, 1H), 8.12 (t, J=5.5Hz, 1H),
5.82 (d, J=6.0Hz, 1H), 5.43 (d, J=6.2Hz, 1H), 5.18 (d, J=4.8Hz, 1H), 5.07 (t, J=5.6Hz, 1H),
4.57 (dd, J=11.3,5.9Hz, 1H), 4.12 (dd, J=8.2,4.8Hz, 1H), 3.93 (dd, J=7.2,3.7Hz, 1H), 3.74
3.60(m,3H),3.58–3.50(m,1H),3.33–3.18(m,2H),2.82–2.65(m,4H),2.10(s,3H)。
Embodiment 13: the synthesis of compound (IV)
Compound III (2.5g, 5.85mmol) and compound VII (29.25mmol) is added separately to 35mL anhydrous acetonitrile
In, then logical nitrogen after being stirred at room temperature 30min in mixed solution, immediately by amyl nitrite (4.25g,
36.3mmol) join in mixed solution, after continuing stirring 10min under room temperature, transfer to 60 DEG C of oil baths are heated 4-8 hour.
After TLC monitoring raw material disappears, decompression evaporates solvent, and residue obtains pale yellow oily liquid body, yield 66% after silicagel column separates.
Claims (10)
1. a synthetic method for cangrelor intermediate shown in formula 6,
Described method comprises the steps: 1) compound 4 is synthesized compound 5 with diazo reagent and halogenating agent；2) change
Compound 5 and 2-(methyl mercapto) ethamine are synthesized compound 5-1；3) compound 5-1 synthesizes compound 6 through hydrolysis；
Wherein X is halogen, and R is alkyl-carbonyl.
Method the most according to claim 1, it is characterised in that described compound 4 is substituted and esterification system by compound 2
:
Wherein R is alkyl-carbonyl.
Method the most according to claim 1 and 2, it is characterised in that described step 1) in diazo reagent be nitrites.
Method the most according to claim 3, it is characterised in that described diazo reagent is amyl nitrite or the tertiary fourth of nitrous acid
Ester.
Method the most according to claim 1 and 2, it is characterised in that described step 1) in halogenating agent be copper halide or halogen
For alkane.
Method the most according to claim 5, it is characterised in that described halogenating agent is copper bromide.
7. according to the method described in claim 1-5, it is characterised in that described step 1) use one pot reaction, reaction temperature is
30-50℃。
Method the most according to claim 1 and 2, it is characterised in that described step 2) carry out in the basic conditions, described alkali
For triethylamine, N-methylmorpholine, sodium acetate or N, N-diisopropylethylamine (DIEA).
Method the most according to claim 2, it is characterised in that described esterification is carried out under weak base participates in.
Method the most according to claim 2, it is characterised in that described esterification is carried out at 0-30 DEG C.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106928296A (en) * | 2017-02-06 | 2017-07-07 | 上海华升生物科技有限公司 | A kind of synthetic method of 2 (3,3,3 trifluoropropyl sulfenyl) adenosines |
| CN107973798A (en) * | 2016-10-25 | 2018-05-01 | 上海医药工业研究院 | 2- [(3,3,3- trifluoro propyls) is thio] -6- amino -9H- purine and preparation method |
| CN107973832A (en) * | 2016-10-25 | 2018-05-01 | 上海医药工业研究院 | The preparation method of 6-N- [2- (methyl mercapto) ethyl] -2- [(3,3,3- trifluoro propyls) is thio] adenosine |
| CN108033983A (en) * | 2018-02-09 | 2018-05-15 | 盐城锦明药业有限公司 | A kind of synthetic method of the thio adenosine of 2- (3,3,3- trifluoro propyls) |
| CN109320574A (en) * | 2017-08-01 | 2019-02-12 | 北京桦冠医药科技有限公司 | A kind of industrialized process for preparing of cangrelor intermediate |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107973798A (en) * | 2016-10-25 | 2018-05-01 | 上海医药工业研究院 | 2- [(3,3,3- trifluoro propyls) is thio] -6- amino -9H- purine and preparation method |
| CN107973832A (en) * | 2016-10-25 | 2018-05-01 | 上海医药工业研究院 | The preparation method of 6-N- [2- (methyl mercapto) ethyl] -2- [(3,3,3- trifluoro propyls) is thio] adenosine |
| 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 |
| CN106928296A (en) * | 2017-02-06 | 2017-07-07 | 上海华升生物科技有限公司 | A kind of synthetic method of 2 (3,3,3 trifluoropropyl sulfenyl) adenosines |
| CN109320574A (en) * | 2017-08-01 | 2019-02-12 | 北京桦冠医药科技有限公司 | A kind of industrialized process for preparing of cangrelor intermediate |
| CN109320574B (en) * | 2017-08-01 | 2021-01-05 | 北京桦冠生物技术有限公司 | Industrial preparation method of cangrelor intermediate |
| CN108033983A (en) * | 2018-02-09 | 2018-05-15 | 盐城锦明药业有限公司 | A kind of synthetic method of the thio adenosine of 2- (3,3,3- trifluoro propyls) |
| CN108033983B (en) * | 2018-02-09 | 2021-06-08 | 盐城锦明药业有限公司 | Synthetic method of 2- (3,3, 3-trifluoropropyl) thioadenosine |
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