CN106496247A - A kind of preparation method of ticagrelor midbody - Google Patents
A kind of preparation method of ticagrelor midbody Download PDFInfo
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- CN106496247A CN106496247A CN201610910764.3A CN201610910764A CN106496247A CN 106496247 A CN106496247 A CN 106496247A CN 201610910764 A CN201610910764 A CN 201610910764A CN 106496247 A CN106496247 A CN 106496247A
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- preparation
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- lyt
- titanium tetrachloride
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- OUGDOCRTXOLCKB-RGFVQRKISA-N CC1(C)O[C@H](C(CC2C3)OC3=N)[C@H]2O1 Chemical compound CC1(C)O[C@H](C(CC2C3)OC3=N)[C@H]2O1 OUGDOCRTXOLCKB-RGFVQRKISA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
Abstract
The invention belongs to technical field of medicine synthesis, is related to a kind of preparation method of ticagrelor midbody, wherein, the method is included under Cu-lyt. catalysis, compound shown in Formulas I and titanium tetrachloride stirring reaction are obtained ticagrelor midbody X, wherein, G is benzyl or substituted benzyl.1 more conventional chloroethylchloroformate ester of the method or P/C hydrogenating reductions, the yield of the compound shown in Formula X have a huge raising, and do not affect for other groups.
Description
Technical field
The invention belongs to technical field of medicine synthesis, is related to a kind of preparation method of ticagrelor midbody.
Background technology
Ticagrelor (Ticagrelor) is a kind of new, selective little point researched and developed by Astrazeneca AB
Sub- anticoagulant, and the oral P2Y12 adenosine diphosphate receptor antagonists of first reversible conjunction type, the blood caused by ADP
The obvious inhibitory action of platelet populated with, can be effectively improved the symptom of acute coronary patient.The medicine was in 2010 and 2011
Listed in European Union and the U.S. by the examination ＆ approval of drug administration of European Union (EMEA) and FDA (Food and Drug Adminstration) (FDA) respectively,
Its import preparation Ticagrelor Tablets has obtained Chinese food pharmaceuticals administration general bureau (SFDA) approval and has listed in China.Ticagrelor
Chemical entitled：(1S, 2S, 3R, 5S) -3- [7- [(1R, 2S) -2- (3,4- difluorophenyls) cyclopropyl amino] -5- (rosickyite base) -
3H-1,2,3- triazols [4,5-d] pyrimidin-3-yl] -5- (2- hydroxyl-oxethyls) Pentamethylene. -1,2- glycol, its structural formula are as follows
Shown：
It is that raw material passes through triphenyl that WO2010069408, WO2012063126 etc. disclose one kind with chiral carbocyclic ring intermediate
Aminating reaction and oxidation, acidolysis, ketalization, reduction, amido protecting, esterification and reduction and deprotection under phosphorus palladium chtalyst etc.
The method of synthesis above-claimed cpd.There is the low defect of route length, yield in the method.
CN102659815B discloses a kind of preparation method of new ticagrelor midbody, the method be related to ingenious, instead
Answer step shorter, the method is initially obtained through multistep reaction with D-ribose as raw material has Complex Chiral Compounds X, operation letter
Just.But in the method, long, reaction yield partially is relatively low the response time the step of particularly debenzylation obtains chipal compounds X, only
Have 50% or so, the application and extension of serious restriction the method are produced greatly.The concrete reaction scheme of the method is as follows：
CN104114542A also discloses a kind of preparation method of ticagrelor midbody, the ingenious utilization N-O miscellaneous six of the method
To obtain the product of specific Stereocenter, the method directly generates open loop product by Pd/C hydrogenating reductions for yuan of rings fixed group position
Thing obtains chiral product, but thus, subsequent reactions also need to each protection and then the selective reaction respectively of hydroxyl, amino, reality
Border increased reactions steps, increase workload.
Therefore, produce to improve said method extension, in addition it is also necessary to a kind of effective debenzylation methods.
Content of the invention
It is an object of the invention to overcoming the low defect of debenzylation yield in said method, there is provided a kind of for shown in Formulas I
Compound and its debenzylation methods of substituted compound, the method are not only able to effectively remove benzyl, moreover it is possible to reduce to other bases
The impact of group, response speed are fast, and high income is conducive to industrialized production.
The present invention provides a kind of preparation method of ticagrelor midbody X, and specifically, the method is included in Cu-lyt. and urges
Under change, the compound shown in Formulas I and titanium tetrachloride stirring reaction are obtained ticagrelor midbody X, it is characterised in that
Wherein, G is benzyl or substituted benzyl.
Although leading in protochloride in said method under catalysis contact the compound shown in Formulas I with titanium tetrachloride, it is
The yield and reaction efficiency of reaction are further improved, and under preferable case, the preparation method is specifically included：First by shown in Formulas I
Compound is mixed in dichloromethane with Cu-lyt., then instills titanium tetrachloride, and stirring reaction obtains ticagrelor midbody
X.
In the present invention, stirring reaction reacts the holding for being more beneficial for other groups at low temperature, such as stirring reaction
Temperature is -15～-10 DEG C.Inventor has found, as temperature is improved, particularly temperature is higher than 0 DEG C, and the yield of reaction does not increase
Long, ketal structure can be destroyed on the contrary so that reaction is mixed and disorderly, purification difficult, and subsequent reactions also need to carry out ketalization, increasing again
Plus workload.Under preferable case, the compound shown in Formulas I is 1 with the consumption mol ratio of titanium tetrachloride, Cu-lyt.：0.6～1：
0.05～0.15.
It is further preferred that the compound shown in Formulas I is 1 with the consumption mol ratio of titanium tetrachloride, Cu-lyt.：0.8～
1：0.1～0.15.
Grade the impact to debenzylation to reduce external water, it is preferable that the stirring reaction is in the presence of protective gas
Carry out, the protective gas is nitrogen, argon or helium etc..
For the compound shown in Formulas I is commercially available or is prepared according to conventional method of the prior art,
For example according to J.Org.Chem., the very easy synthesis of method in 2005,70,6885 or CN102659815B.
The invention has the beneficial effects as follows：The invention provides a kind of raw material of new preparation ticagrelor midbody, specifically
Ground, the invention provides a kind of effective debenzylation methods of compound of formula I, the more conventional 1- chloroethylchloroformates ester of the method or
Person's P/C hydrogenating reductions, the yield of the compound shown in Formula X have a huge raising, and do not affect for other groups, directly
Connect cis hydroxyl groups-amine is obtained for N- substitution reactions or open loop.
Specific embodiment
With reference to specific embodiment, the present invention is described in detail.Following examples will be helpful to the technology of this area
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this area
For personnel, without departing from the inventive concept of the premise, some deformations and improvement can also be made.These belong to the present invention
Protection domain.
Preparation example
The preparation of the compound shown in Formulas I
In reaction vessel, add initiation material A 15.6g (100mmol), benzyl oxammonium hydrochloride. 15.9g (150mmol),
Sodium carbonate 21.2g (200mol), and ethanol is added as reaction dissolvent, it is stirred at room temperature 1 hour, TLC monitoring reactions terminate, and react
Liquid is filtered, filtrate reduced in volume；Concentrating under reduced pressure product is transferred in dimethylbenzene, 135 DEG C are warming up to, back flow reaction, TLC are supervised
Survey, after reaction terminates, reactant liquor concentrating under reduced pressure, dichloromethane dissolve, and wash three times, and organic faciess are concentrated, and petroleum ether recrystallization is obtained
To the compound 19.9g shown in Formulas I, purity 99.20%, yield 74.3%.
Embodiment 1
In flask, system replaces nitrogen, adds compound and 1g (0.01mol) chlorine shown in 26.1g (0.1mol) Formulas I
Change cuprous and 100ml dichloromethane, it is -10 DEG C to reduce temperature, then instills 18.9g (0.1mol) titanium tetrachloride, and stirring is anti-
Answer 5 hours, TLC monitoring reactions are finished, and reactant liquor is warmed to room temperature naturally, add water, layering, organic layer to wash three times, anhydrous sulfur
Sour sodium is dried, concentrating under reduced pressure, is then recrystallized to give ticagrelor midbody X 14.9g in petroleum ether, yield 87.4%,
HPLC purity 99.15% (area normalization method).
HNMR (400MHz, d6-DMSO) 4.98 (s, 1H), 4.62 (d, 1H, J=5.6Hz), 4.50 (s, 1H), 4.26 (d,
1H, J=5.6Hz), 2.21 (d, 1H, J=12.4Hz), 1.92 (d, 1H, J=12.4Hz), 1.39 (s, 3H), 1.27 (s, 3H).
Embodiment 2
In flask, system replaces nitrogen, adds compound and 0.8g shown in 26.1g (0.1mol) Formulas I
(0.008mol) Cu-lyt. and 80ml dichloromethane, it is -15 DEG C to reduce temperature, then instills 15.2g (0.08mol) tetrachloro
Change titanium, stirring reaction 4 hours, TLC monitoring reactions are finished, and reactant liquor is warmed to room temperature naturally, add water, layering, organic layer to wash
Three times, then anhydrous sodium sulfate drying, concentrating under reduced pressure are recrystallized to give ticagrelor midbody X 14.8g in petroleum ether, receive
Rate 86.7%, HPLC purity 98.88% (area normalization method).
Embodiment 3
In flask, system replaces nitrogen, adds compound and 3g (0.03mol) shown in 52.2g (0.2mmol) Formulas I
Cu-lyt. and 100ml dichloromethane, it is -10 DEG C to reduce temperature, then instills 17.1g (0.09mol) titanium tetrachloride, stirring
Reaction 5 hours, TLC monitoring reactions are finished, and reactant liquor is warmed to room temperature naturally, add water, and layering, organic layer are washed three times, anhydrous
Sodium sulfate is dried, and then concentrating under reduced pressure is recrystallized to give ticagrelor midbody X 14.6g in petroleum ether, yield 85.1%,
HPLC purity 99.20% (area normalization method).
Embodiment 4
In flask, system replaces nitrogen, adds compound and 1g (0.01mol) chlorine shown in 26.1g (0.1mol) Formulas I
Change cuprous and 100ml dichloromethane, it is -10 DEG C to reduce temperature, then instills 11.4g (0.06mol) titanium tetrachloride, and stirring is anti-
Answer 4～5 hours, TLC monitoring reactions are finished, and reactant liquor is warmed to room temperature naturally, add water, and layering, organic layer are washed three times, anhydrous
Sodium sulfate is dried, and then concentrating under reduced pressure is recrystallized to give ticagrelor midbody X 14.1g in petroleum ether, yield 82.2%,
HPLC purity 99.07% (area normalization method).
Embodiment 5
In flask, system replaces nitrogen, adds compound and 0.5g shown in 26.1g (0.1mol) Formulas I
(0.005mol) Cu-lyt. and 80ml dichloromethane, it is -15 DEG C to reduce temperature, then instills 11.4g (0.06mol) tetrachloro
Change titanium, stirring reaction 5 hours, TLC monitoring reactions are finished, and reactant liquor is warmed to room temperature naturally, add water, layering, organic layer to wash
Three times, then anhydrous sodium sulfate drying, concentrating under reduced pressure are recrystallized to give ticagrelor midbody X 13.9g in petroleum ether, receive
Rate 81.6%, HPLC purity 98.78% (area normalization method).
Comparative example
Compound shown in 26.1g (0.1mol) Formulas I, 2.6g Pd/C, 100ml methanol are added in reactor, are passed through
10 bar of hydrogen, 25 DEG C of stirring reactions 10～14 hours, the compound reaction shown in TLC monitoring Formulas I are finished, and are filtered, column chromatography point
From ticagrelor midbody X3.4g, yield 19.6%, other by-products are deprotection glycol and open loop (N, O heterocycle) product.
Claims (6)
1. a kind of preparation method of ticagrelor midbody, it is characterised in that the method is included under Cu-lyt. catalysis, by formula
Compound shown in I obtains ticagrelor midbody X with titanium tetrachloride stirring reaction,
Wherein, G is benzyl or substituted benzyl.
2. preparation method as claimed in claim 1, it is characterised in that the preparation method is specifically included：First by the change shown in Formulas I
Compound is mixed in dichloromethane with Cu-lyt., then instills titanium tetrachloride, and reaction obtains ticagrelor midbody X.
3. the preparation method as described in claim 1-2, it is characterised in that the temperature of stirring reaction is -15～-10 DEG C, Formulas I institute
The compound for showing is 1 with the consumption mol ratio of titanium tetrachloride, Cu-lyt.：0.6～1：0.05～0.15.
4. preparation method as claimed in claim 3, it is characterised in that the compound shown in Formulas I and titanium tetrachloride, Cu-lyt.
Consumption mol ratio be 1：0.8～1：0.1～0.15.
5. preparation method as claimed in claim 4, it is characterised in that the compound shown in Formulas I and titanium tetrachloride, Cu-lyt.
Consumption mol ratio be 1：1：0.1.
6. the preparation method as described in claim 1-5, it is characterised in that the stirring reaction is entered in the presence of protective gas
OK, the protective gas is nitrogen, argon or helium etc..
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659815A (en) * | 2012-05-04 | 2012-09-12 | 开原亨泰制药股份有限公司 | Method for preparing selective anticoagulant ticagrelor and intermediates thereof |
| CN103923055A (en) * | 2014-04-02 | 2014-07-16 | 黄河三角洲京博化工研究院有限公司 | preparation method of (1S,2R,3S,4R)-2,3-O-isopropylidene-4-aminocyclopentyl-1,2,3-triol |
-
2016
- 2016-10-19 CN CN201610910764.3A patent/CN106496247A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659815A (en) * | 2012-05-04 | 2012-09-12 | 开原亨泰制药股份有限公司 | Method for preparing selective anticoagulant ticagrelor and intermediates thereof |
| CN103923055A (en) * | 2014-04-02 | 2014-07-16 | 黄河三角洲京博化工研究院有限公司 | preparation method of (1S,2R,3S,4R)-2,3-O-isopropylidene-4-aminocyclopentyl-1,2,3-triol |
Non-Patent Citations (3)
| Title |
|---|
| BROCK T. SHIREMAN等，: "Rapid syntheses of either enantiomer of important carbocyclic nucleoside precursors", 《TETRAHEDRON LETTERS》 * |
| CHUN-CHIEH LIN等: "Novel Asymmetric Route to Carbanucleoside and Prostanoid Intermediates: Efficient Preparation of Both Optical Antipodes of Chiral Cyclopentenone", 《J. ORG. CHEM.》 * |
| 杨光富主编: "《有机合成》", 30 November 2010 * |
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Application publication date: 20170315 |