CN103539773B - Method for preparing ticagrelor key intermediate - Google Patents
Method for preparing ticagrelor key intermediate Download PDFInfo
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- CN103539773B CN103539773B CN201310440149.7A CN201310440149A CN103539773B CN 103539773 B CN103539773 B CN 103539773B CN 201310440149 A CN201310440149 A CN 201310440149A CN 103539773 B CN103539773 B CN 103539773B
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- 0 CC1O[C@@](*(CCC2(C3)C3OCCOC)*(*=O)C(*C3=C(C)C=CCC=C3)=O)[C@@]2OC1C Chemical compound CC1O[C@@](*(CCC2(C3)C3OCCOC)*(*=O)C(*C3=C(C)C=CCC=C3)=O)[C@@]2OC1C 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a new method for preparing a ticagrelor key intermediate I. The method comprises the steps of performing O-alkylation on an intermediate II by using ethylene sulfate and glycol sulfite, and then depriving the amino protecting group to obtain the ticagrelor key intermediate I. Raw materials involved with the method are cheap and easily available; the method is mild in reaction conditions and friendly to the environment, and has good industrial production prospect.
Description
Technical field
The invention belongs to technical field of organic synthesis.Be specially a kind of brand-new synthetic method of anticoagulant ticagrelor key intermediate.
Background technology
Ticagrelor, English name: Ticagrelor; Once use code name: ADZ6140, AR-C126532, belong to cyclopentyl triazolopyrimidines, chemistry (1S by name, 2S, 3R, 5S)-3-[7-[(1R, 2S)-2-(3,4-dichlorophenyl) cyclopropylamino]-5-(thiopropyl)-3H-[1,2,3] triazole [4,5-d] pyrimidin-3-yl]-5-(2-hydroxyl-oxethyl) pentamethylene-1,2-glycol.This medicine be by U.S.'s AstraZeneca (AstraZeneca) company research and develop a kind of novel, there is optionally small molecules anticoagulant.This medicine can purine 2 acceptor (purinoceptor2 reversibly on vasoactive smooth muscle cell (VSMC), P2) hypotype P2Y12, obvious restraining effect is had to the platelet aggregation that ADP causes, and it is rapid to orally use rear onset, therefore effectively can improve the symptom of acute coronary patient.And because of the antiplatelet effects of ticagrelor be reversible, its for those need after carrying out anticoagulant therapy in advance again row operation patient particularly applicable.It is significantly to reduce the death that cardiovascular origin and all reasons cause that ticagrelor compares the most attractive advantage of its rival's clopidogrel.It is a kind of anticoagulant had a extensive future.
Compound I is one of important intermediate preparing ticagrelor.WO2012172426, WO2001092263 etc. are comprised in the patent documentation that the synthetic method of Compound I is relevant in prior art.
WO2012172426 reports route with compound 1 for raw material, obtains the compound 2 of Cbz protection through the protection of N-acyl group; Then carry out substitution reaction with ethyl bromoacetate, lithium borohydride reduction reaction obtains 3; Last hydro-reduction obtains intermediate compound I
When above route introduces hydroxyethyl, the method substantially used is two steps:
1) hydroxyl and halogenated acetic acids ester react;
2) go back ortho-acetate and obtain hydroxyethyl.
The reduction reaction energy consumption of intermediate is large, aftertreatment is complicated, danger is large to adopt the method to prepare.
Summary of the invention
The technical problem that invention will solve: a kind of method preparing ticagrelor key intermediate I is provided, the method adopts sulfuric acid vinyl ester or ethylene sulfite directly to carry out alkylation to hydroxyl, and raw material is cheaply easy to get, and reaction conditions is gentle, environmental friendliness, has good industrial production prospect.
The technical scheme that technical solution problem is taked: a kind of method preparing ticagrelor key intermediate I, the method comprises:
1) take Compound II per as raw material, react with compound III a or IIIb in the basic conditions;
2) O-sulfuric ester or the protection of O-sulfite is removed;
3) remove amino protecting group, obtain Compound I;
Wherein R
1r
2can be formed as various amino protecting group, the amino protecting groups such as such as carbobenzoxy-(Cbz), phthaloyl, benzyl, this type of protecting group can remove in subsequent reactions easily.
When adopting IIIa as reaction substrate, all can carry out in two phase reaction and homogeneous reaction with the reaction of Compound II per.When adopting two phase reaction, reaction solvent can select THF/H
2o, DCM/H
2o etc., the alkali used is alkali-metal oxyhydroxide, is preferably sodium hydroxide; When adopting homogeneous reaction, the solvent used can be THF, DMF, DMSO equal solvent, and the alkali used can be alkali alcoholate and sodium hydrogen, potassium hydrogen etc., and when adopting THF as reaction solvent, preferred alkali is potassium tert.-butoxide; When adopting DMF to make solvent, preferred alkali is sodium hydrogen.
After adopting IIIa to obtain O-alkylated intermediate IV as substrate, can in last handling process, multiple acidic aqueous solution be directly used to remove sulfuric ester, obtain compound V, spendable acid is the trifluoromethanesulfonic acid etc. of hydrochloric acid, sulfuric acid, formic acid and different concns, and preferably the aqueous formic acid of 40% removes sulfuric ester.
When adopting IIIa as substrate, amino protecting group R
1r
2(CH can be selected
2ph)
2, carbobenzoxy-(Cbz), the protecting group such as phthaloyl, preferred protecting group is phthaloyl.
When adopting IIIb as reaction substrate, carry out in homogeneous reaction with the reaction of Compound II per, solvent can be THF, DMF etc., and alkali used can be sodium hydrogen, sodium amide etc., and result of study shows to adopt alkali metal alcoholates not react.
After adopting IIIb to obtain O-alkylated intermediate as substrate, can directly obtain compound V through last handling process.
When adopting IIIa as substrate, amino protecting group R
1r
2(CH can be selected
2ph)
2, carbobenzoxy-(Cbz), the protecting group such as phthaloyl, preferred protecting group is carbobenzoxy-(Cbz).
When adopting IIIb as substrate, amino protecting group R
1r
2(CH can be selected
2ph)
2, carbobenzoxy-(Cbz), the protecting group such as phthaloyl, preferred protecting group is phthaloyl.
On the basis of above research, the invention discloses two new synthesis routes of ticagrelor key intermediate I, adopt the method efficiently, with high yield can obtain intermediate compound I.Concrete route is as follows:
Synthetic route 1:
Synthetic route 2:
Wherein 1 preparation can reference (
j. Org. Chem.70,6885,2005;
j. Org. Chem.55,3853,1990) method in is prepared by starting raw material with D-ribose.
Beneficial effect: the method preparing ticagrelor key intermediate I of the present invention adopts sulfuric acid vinyl ester or ethylene sulfite directly to carry out alkylation to hydroxyl, eliminate the reduction reaction that wherein energy consumption is large, aftertreatment is complicated, danger is large, the method raw material preparing ticagrelor key intermediate I of the present invention is cheaply easy to get, reaction conditions is gentle, environmental friendliness, obvious economic advantages, are more suitable for industrialized production.
Embodiment
What below enumerate is only several specific embodiments of the present invention, the invention is not restricted to following examples, also has many distortion.All distortion that those of ordinary skill in the art can directly derive from content disclosed by the invention or associate, all should think protection scope of the present invention.
Embodiment 1 [3aS-(3a α, 4 α, 6 α, 6a α)]-[2,2-dimethyl-6-(hydroxyethyl) preparation of-tetrahydrochysene-4H-ring penta-DOX-4 bases-carboxylamine-benzyl methyl esters
Compound 2(1 g is added, 3.25 mmol, 1 eq. in the there-necked flask of drying) and anhydrous tetrahydro furan (20 mL).Be cooled to 0 DEG C, add potassium tert.-butoxide (0.73 g, 6.51 mmol, 2 eq.) under nitrogen protection, and stirring added 1,3,2-bis-oxazole thiophene-2,2-dioxide (IIIa) after 2 hours at this temperature, at room temperature stir 1 hour.After reacting completely, add the vitriol oil (2 mL) in reaction solution, stir 5 minutes, intermediate 4 reacts completely.Reaction solution is concentrated into dry except desolventizing, through dehydrated alcohol recrystallization, obtains white solid 3.Output: 0.45 g, yield: 39%.
1HNMR(400MHz,CDCl
3), δ7.31(m,5H), 5.74(d,1H)，5.11(d，2H)，4.55(m，2H)，4.17(m,1H)，3.88(m,1H)，3.72(m,2H)，3.61(m,2H)，2.19(m,1H)，1.80(d,1H)，1.41(s,3H)，1.22(S,1H)。
The preparation of embodiment 2 [3aR-(3a α, 4 α, 6 α, 6a α)]-2-[[amino-2,2-dimethyl-tetrahydro-4H-ring penta-DOX-4 bases of 6-] oxo]-ethanol
Compound 3(4g, 5.7mmol) be dissolved in dehydrated alcohol (20mL), add the palladium carbon of 10% of catalytic amount, stir under nitrogen atmosphere and spend the night, TLC detection reaction is filtered completely afterwards, filter cake anhydrous methanol washs three times, and filtrate concentrates to obtain compound 10, light yellow oil (TLC:DCM: MeOH=8:1).Output: 2.2g, productive rate: 93%.
1H NMR (400 MHz, CDCl
3) δ 4.57 (d, 1H), 4.37 (d, 1H), 3.79 (d, 1H), 3.61 – 3.46 (m, 4H), 3.26 (d, 1H), 3.02 (s, 3H), 2.10 - 2.01 (m, 1H), 1.73 (d, 1H), 1.33 (s, 3H), 1.20 (s, 3H).。
The preparation of embodiment 3 2-[(3aS, 4R, 6S, 6aR)-6-hydroxyl-2,2-dimethyl-tetrahydro-3aH-ring penta [d] [1,3] dioxolane-4-alcohol] isoindoline-1,3-diketone
In vexed tank, add 1(3g, 17.3 mmol, 1 eq.), Tetra hydro Phthalic anhydride (2.6g, 17.3mmol, 1 eq.) and DIPEA(3.7mL, 22.5mmol, 1.3 eq.), and at 140 DEG C confined reaction 5 hours.Be cooled to room temperature, add methylene dichloride and water, layering in reaction solution, collect organic phase, dry filter, concentrate and obtain crude product, column chromatography obtains solid 2g, yield: 40%.
1HNMR(400MHz, CDCl
3):7.89(m，2H)，7.78(m，2H)，5.11(m，1H)，4.73(m，2H)，4.32(m，1H)，3.75(d，1H)，2.67(m，1H)，2.01(m，1H)，1.52(s，3H)，1.27(s，3H) 。
Embodiment 4 [3aS-(3a α, 4 α, 6 α, 6a α)]-[6-(2-hydroxyl-oxethyl)-2,2-dimethyl-tetrahydrochysene-3AH-cyclopenta [d] [1,3] dioxole-4-Ji) preparation of isoindoline-1,3-diketone
Compound 5(1g, 3.3mmol, 1eq.) be dissolved in dry DMF (10mL), add sodium hydrogen (195mg, 4.9mmol, 1.5eq.) at-10 DEG C, and stir 1 hour at this temperature.In reaction solution, add glycol sulfite (IIIb, 1.59g, 14.7mmol, 4.5eq.), rise to room temperature, stirring is spent the night.Add saturated potassium dihydrogen phosphate aqueous solution cancellation reaction, extraction into ethyl acetate layering, organic layer is washed, dry, concentrated, the compound 6(0.5g that column chromatography purification obtains), yield: 45.5%.
1HNMR(400MHz,CDCl
3)： 7.82(m,2H), 7.70(m,2H), 5.28(m, 1H), 4.71(m, 2H), 3.91(m, 1H), 3.69 (m, 3H), 3.59 (m, 1H), 2.38 (m, 2H), 1.52 (s, 3H), 1.28 (s, 3H)。
Embodiment 5 [3aS-(3a α, 4 α, 6 α, 6a α)]-[6-(2-hydroxyl-oxethyl)-2,2-dimethyl-tetrahydrochysene-3AH-cyclopenta [d] [1,3] dioxole-4-Ji) preparation of isoindoline-1,3-diketone
Compound 5(0.5g, 1.65mmol, 1eq.) be dissolved in dry DMF (2mL), add the DMF solution of sodium amide (103mg, 2.64mmol, 1.6eq.) at-10 DEG C, and stir 1 hour at this temperature.In reaction solution, add glycol sulfite (IIIb, 1.78g, 16.5mmol, 10eq.), stir 1 hour at this temperature.Add saturated potassium dihydrogen phosphate aqueous solution cancellation reaction, extraction into ethyl acetate layering, organic layer is washed, dry, concentrated, the compound 6(0.2g that column chromatography purification obtains), yield: 35%.
The preparation of embodiment 6 [3aR-(3a α, 4 α, 6 α, 6a α)]-2-[[amino-2,2-dimethyl-tetrahydro-4H-ring penta-DOX-4 bases of 6-] oxo]-ethanol
6(100 mg) be dissolved in ethanol (2mL), add hydrazine hydrate (0.2mL), heat 2 hours, have solid to separate out at 70 DEG C, filter, obtain filtrate, be concentrated into dry, column chromatography purification obtains compound 7(40mg), yield: 64%.
1HNMR(400MHz,CDCl
3): 4.59(d,1H), 4.40(d,1H), 3.81(m,1H), 3.58(m,3H), 3.32(d,1H), 2.04(m,1H), 1.75(m,1H), 1.38(s,3H), 1.22(s,3H)。
Embodiment 7 [3aS-(3a α, 4 α, 6 α, 6a α)]-[2,2-dimethyl-6-(hydroxyethyl) preparation of-tetrahydrochysene-4H-ring penta-DOX-4 bases-carboxylamine-benzyl methyl esters
Compound 1(500mg) be dissolved in chloroform (15mL), add aqueous sodium hydroxide solution (2eq., 15mL), then 1,3,2-bis-oxazole thiophene-2 is added successively, 2-dioxide (IIIa, 2eq) and TBAB(0.1eq), reaction solution heats 1 hour at 60 DEG C.After reacting completely, add the vitriol oil (1 mL) in reaction solution, stir 5 minutes, intermediate 2 reacts completely.Reaction solution is concentrated into dry except desolventizing, through dehydrated alcohol recrystallization, obtains white solid 3.Output: 0.15 g, yield: 25%.
Claims (6)
1. prepare a method of ticagrelor key intermediate I, it is characterized in that: the method comprises:
1) take Compound II per as raw material, react with compound III a or IIIb in the basic conditions,
2) O-sulfuric ester or the protection of O-sulfite is removed;
3) remove amino protecting group, obtain Compound I;
R
1during for carbobenzoxy-(Cbz), R
2for hydrogen; Or R
1r
2for phthaloyl.
2. the method preparing ticagrelor key intermediate I according to claim 1, is characterized in that: the method comprises:
1) take Compound II per as raw material, react with compound III a under alkaline condition;
2) remove the protection of O-sulfuric ester, obtain compound V;
3) remove amino protecting group, obtain Compound I.
3. the method preparing ticagrelor key intermediate I according to claim 1, is characterized in that: the method comprises:
1) take Compound II per as raw material, react with compound III b in the basic conditions, obtain compound V;
2) remove amino protecting group, obtain Compound I.
4. the method preparing ticagrelor key intermediate I according to claim 2, is characterized in that: under alkali metal hydroxide effect, carry out two phase reaction, described alkali is sodium hydroxide.
5. the method preparing ticagrelor key intermediate I according to claim 2, is characterized in that: under alkali metal alcohol salt action, carry out homogeneous reaction, described alkali is sodium tert-butoxide.
6. the method preparing ticagrelor key intermediate I according to claim 3, is characterized in that: the alkali used is sodium hydrogen, potassium hydrogen or sodium amide.
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| CN108503642A (en) * | 2018-04-29 | 2018-09-07 | 安徽海康药业有限责任公司 | A kind of preparation method of high-purity single acetyl Ganciclovir |
| CN108689984B (en) * | 2018-05-02 | 2019-09-20 | 淮阴工学院 | A kind of biological synthesis method and its intermediate of ticagrelor intermediate |
| CN112724119B (en) * | 2020-12-30 | 2022-05-03 | 江苏恒沛药物科技有限公司 | Synthesis method of ticagrelor key intermediate |
| CN113801090B (en) * | 2021-11-18 | 2022-02-18 | 南京威凯尔生物医药科技有限公司 | Ticagrelor key intermediate and preparation method thereof |
| CN115894430A (en) * | 2022-11-24 | 2023-04-04 | 四川青木制药有限公司 | Preparation method of ticagrelor key intermediate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012172426A1 (en) * | 2011-06-15 | 2012-12-20 | Actavis Group Ptc Ehf | Improved process for preparing cyclopentylamine derivatives and intermediates thereof |
| WO2013037942A1 (en) * | 2011-09-14 | 2013-03-21 | Lek Pharmaceuticals D.D. | Synthesis of triazolopyrimidine compounds |
-
2013
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012172426A1 (en) * | 2011-06-15 | 2012-12-20 | Actavis Group Ptc Ehf | Improved process for preparing cyclopentylamine derivatives and intermediates thereof |
| WO2013037942A1 (en) * | 2011-09-14 | 2013-03-21 | Lek Pharmaceuticals D.D. | Synthesis of triazolopyrimidine compounds |
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