CN103073525B - Method for synthesizing (S)-(3,4-difluorophenyl)hexamethylene oxide - Google Patents
Method for synthesizing (S)-(3,4-difluorophenyl)hexamethylene oxide Download PDFInfo
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- CN103073525B CN103073525B CN201310043982.8A CN201310043982A CN103073525B CN 103073525 B CN103073525 B CN 103073525B CN 201310043982 A CN201310043982 A CN 201310043982A CN 103073525 B CN103073525 B CN 103073525B
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Abstract
The invention relates to a method for chiral synthesis of a (S)-(3,4-difluorophenyl)ethylene oxide intermediate. The method comprises the following steps: (1) performing Sharpless asymmetric dihydroxylation (AD) reaction on 3,4-difluorostyrene by taking t-BuOH/H2O as a solvent and AD-mix-alpha as an oxidant at the presence of methane sulfonamide to obtain (S)-(3,4-difluorophenyl)glycol; (2) mixing the (S)-(3,4-difluorophenyl)glycol and triethyl orthoacetate by a one-pot method, and condensing at a certain temperature to obtain a cyclic condensate intermediate; (3) mixing the cyclic condensate intermediate and a bromine reagent, reacting, adding water, separating out an organic layer, and treating to obtain a bromide intermediate; and (4) heating the bromide intermediate in the step (3) in an organic solvent at the presence of anhydrous potassium carbonate to react so as to obtain the (S)-(3,4-difluorophenyl)ethylene oxide target.
Description
technical field:
The invention belongs to medicinal chemistry art, particularly a kind of chiral synthesize preparation (
s)-(3,4-difluorophenyl) method of polyethylene oxide intermediate.Crucial chiral raw material required when this chiral intermediate is ADZ6140 synthesis.
background technology:
ADZ6140 (ticagrelon) (as shown in Equation 1) is a kind of selectivity small molecules anticoagulation medicine.Be reversibly to act on P2Y
12acceptor, has stronger restraining effect to the platelet aggregation that adenosine diphosphate (ADP) (ADP) causes, and oral rear rapid-onset, obviously can improve the symptom of acute coronary.When building the structure of ADZ6140, (
1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (as shown in Equation 2) is a kind of chiral intermediate building block of key.The synthesis of this cyclopropylamine building block can use (
s)-3,4-difluorophenyl oxyethane are chiral starting materials.
formula (1)
formula (2)
Existing document [1] report, through (
s)-3,4 two-fluorophenyl polyethylene oxide intermediate, synthesize (
1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine (Jean-Paul D; Koen P Marc R. WO 2008018822,2008-02-
14 and Masaru M.; Tadashi M; Kentaro T; Et al .WO 2008018823,2008-02-14 and Singh A K; Rao M N; Simpson J H; Et al, Org. Process Res. Dev. 2002,6,618-620. and Zhang H; Liu; Zhang L .Y; Et al .Bioorg. Med. Chem. Lett., 2012,22,3598-
3602.）。The core of these report route methods is with prochiral ketone precursor for raw material, through the reduction of prochiral ketone precursor under chiral induction agent exists, generates chiral alcohol derivative, then becomes ring to generate chiral epoxy compound.The chiral epoxy compound generated, Cyclopropanated through Wadsworth-Emmons, generate chiral cyclopropane sulfonamide derivatives, namely (
1R, 2S)-2-(3,4-difluorophenyl) cyclopropylamine.These method routes are brief, and more direct during structure chiral centre, the optical purity of chiral material is higher.Its route methods is as being shown in accompanying drawing 1.
But, above-mentioned document synthesis (
s) chloro-1-(3, the 4-difluorophenyl of-2-) and ethanol time, still need use BH
3-Me
2s reductive agent, and (
s)-phenylbenzene Prolinol price is also more valuable.So, seek easy, reaction conditions gentle, chiral epoxy compound preparation method with low cost is of great significance.
summary of the invention:
The object of the invention is to propose a kind of (
s)-3, the new synthetic method of 4-difluorophenyl oxyethane, so that with it for chiral raw material, can synthesize the chiral intermediate building block (1R of ADZ6140 key under condition easy, that reaction conditions is gentle, with low cost, 2S)-2-(3,4-difluorophenyl) cyclopropylamine.
The present invention's proposition (
s) the synthetic method route of-3,4 difluorophenyl oxyethane is shown in accompanying drawing 2.
A kind of method of synthesis preparation (S)-3,4-fluorophenyl oxepane, it is characterized in that, synthesis step is as follows:
(1) under Toluidrin exists, with
t-buOH/H
2o is solvent, and AD-mix-α is oxygenant, 3,4-difluorobenzene ethene is carried out to the AD reaction of Sharpless, generate (
s)-(3,4-difluorophenyl) ethylene glycol;
(2) incite somebody to action (
s)-(3,4-difluorophenyl) ethylene glycol " one kettle way " and triethly orthoacetate mixing, after reacting condensation under certain temperature, obtain ring-shaped condensate intermediate;
(3) by this ring-type shape condenses intermediate and bromide reagent mixing, reaction, adds water after completing, separates organic layer, treated bromo-derivative intermediate;
(4) step (3) gained bromide intermediate is in organic solvent, reacting by heating under Anhydrous potassium carbonate exists, obtain (
s)-(3,4-difluorophenyl) oxyethane.
Further, in described step (2), be by (
s)-(3,4-difluorophenyl) ethylene glycol first with triethly orthoacetate mixing, 10 DEG C--react at 100 DEG C, after reaction condensation, steam except excessive triethly orthoacetate, obtain ring-shaped condensate intermediate.
Further, described step (3) temperature of reaction is 10 DEG C--100 DEG C.
Further, described step (3) bromide reagent is acetyl bromide or bromotrimethylsilane.
Further, in described step (4), organic solvent used is methyl alcohol, ethanol, acetonitrile polar solvent.
The invention has the advantages that: reactions steps is short, reaction conditions is gentle, and products therefrom optical purity is high.
Accompanying drawing explanation
Fig. 1 be background technology Literature [1] (
s)-3,4-difluorophenyl ethylene oxide synthesis route maps.
Fig. 2 is method synthetic route chart of the present invention.
embodiment:
Embodiment 1:
(1) in reaction vessel, put into
t-buOH/H
2o(10ml, v/v=1:1), AD-mix-α (2.0g), mix and blend, after 15 minutes, adds Toluidrin (158mg, 1.66mmol), then adds 3,4-difluorobenzene ethene (193mg, 1.38mmol) stirred at ambient temperature after stirring 15 minutes 24 hours.Add S-WAT 2.0g, continue stirring 1 hour, reaction mixture use water (30ml) processes, CH
2cl
2extraction (3 × 50ml), merges organic phase, dried over mgso.After removal of solvent under reduced pressure, obtain solids 216mg, yield 90 ﹪.
1H NMR (CDCl
3, 400MH
Z ), δ：7.01-7.04（m，3H），4.57-4.59（m，1H），4.10-4.14(m，1H), 3.87-3.87(m，1H)。
(2) by (24.7g, 0.142mol) (
s)-(3,4-difluorophenyl) ethylene glycol, 70ml methylene dichloride drops in there-necked flask, and stirring and dissolving is warming up to 50 DEG C, adds 25.27 grams of triethly orthoacetates, and react after one hour, termination reaction, steams low-boiling point material, obtains 34 grams, ring-shaped condensate intermediate.Without purifying, be directly used in the next step, yield 100%.
34 grams, above-mentioned ring-shaped condensate intermediate is dissolved in 50ml methylene dichloride, after adding acetyl bromide 19.18 grams reaction 2h, 70ml water termination reaction is added in system, collected organic layer, water layer uses dichloromethane extraction secondary again, dried over mgso, obtains viscous material 35.6 grams, yield 90% after decompression removing methylene dichloride.I.e. bromo-derivative.
Above-mentioned bromo-derivative 35.6 grams, 70ml methyl alcohol, Anhydrous potassium carbonate, back flow reaction 1h, after completing reaction, decompression steams methyl alcohol, and resistates is dissolved in 70ml methylene dichloride, adds 30ml water, washes twice.Organic layer adds dried over mgso.Decompression steams methylene dichloride.Under reduced pressure distill, collect 70-73 degree fraction/10mmHg, obtain product 17.7 grams, yield 80%, namely (
s)-(3,4-difluorophenyl) oxyethane.
Embodiment 2:
(1) in reaction vessel, put into
t-buOH/H
2o(5ml, v/v=1:1), AD-mix-α (1.0g),
Mix and blend, after 15 minutes, adds Toluidrin (79mg, 0.83mmol), then adds 3,4-difluorobenzene ethene (96.5mg, 0.69mmol) stirred at ambient temperature after stirring 15 minutes 24 hours.Add S-WAT 1.0g, continue stirring 1 hour, reaction mixture use water (15ml) processes, CH
2cl
2extraction (3 × 50ml), merges organic phase, dried over mgso.After removal of solvent under reduced pressure, obtain solids 104.4mg, yield 87 ﹪.
1H NMR (CDCl
3, 400MH
Z ), δ：7.01-7.02（m，3H），4.56-4.60（m，1H），4.12-4.15(m，1H), 3.88-3.89(m，1H)。
(2) by (12.4g, 0.071mol) (
s)-(3,4-difluorophenyl) ethylene glycol, 35ml methylene dichloride drops in there-necked flask, and stirring and dissolving is warming up to 50 DEG C, adds 12.64 grams of triethly orthoacetates, and react after one hour, termination reaction, steams low-boiling point material, obtains 17 grams, ring-shaped condensate intermediate.Without purifying, be directly used in the next step, yield 100%.
17 grams, above-mentioned ring-shaped condensate intermediate is dissolved in 50ml methylene dichloride, after adding bromotrimethylsilane 10.86 grams reaction 2h, 35ml water termination reaction is added in system, collected organic layer, water layer uses dichloromethane extraction secondary again, dried over mgso, obtains viscous material 17.8 grams, yield 90% after decompression removing methylene dichloride.I.e. bromo-derivative.
Above-mentioned bromo-derivative 17.8 grams, 35ml ethanol, Anhydrous potassium carbonate, back flow reaction 1h, after completing reaction, decompression steams ethanol, and resistates is dissolved in 35ml methylene dichloride, adds 15ml water, washes twice.Organic layer adds dried over mgso.Decompression steams methylene dichloride.Under reduced pressure distill, collect 72-75 degree fraction/10mmHg, obtain product 8.9 grams, yield 80%, namely (
s)-(3,4-difluorophenyl) oxyethane.
Claims (4)
1. the method for synthesis preparation (S)-(3, a 4-difluorophenyl) oxepane, it is characterized in that, synthesis step is as follows:
(1) under Toluidrin exists, with t-BuOH/H
2o is solvent, and AD-mix-α is oxygenant, 3,4-difluorobenzene ethene is carried out to the AD reaction of Sharpless, generates (S) – (3,4-difluorophenyl) ethylene glycol;
(2) first (S)-(3,4-difluorophenyl) ethylene glycol is mixed with triethly orthoacetate, react at 10 DEG C-100 DEG C, after reaction condensation, steam except excessive triethly orthoacetate, obtain ring-shaped condensate intermediate;
(3) by this ring-shaped condensate intermediate and bromide reagent mixing, reaction, adds water after completing, separates organic layer, treated bromo-derivative intermediate;
(4) step (3) gained bromide intermediate in organic solvent, and reacting by heating under Anhydrous potassium carbonate exists, obtains (S)-(3,4-difluorophenyl) oxyethane.
2. the method according to right 1, is characterized in that: described step (3) temperature of reaction is 10 DEG C-100 DEG C.
3. the method according to right 1, is characterized in that: described step (3) bromide reagent is acetyl bromide or bromotrimethylsilane.
4. the method according to right 1, is characterized in that: in described step (4), and organic solvent used is methyl alcohol, ethanol, acetonitrile polar solvent.
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| CN105671099A (en) * | 2016-01-26 | 2016-06-15 | 中国科学院成都生物研究所 | Method for preparing optical pure difluorophenyl ethylene oxide |
| CN115710158A (en) * | 2021-08-23 | 2023-02-24 | 凯特立斯（深圳）科技有限公司 | Method for preparing ticagrelor intermediate through asymmetric catalysis |
| CN115894496A (en) * | 2021-09-30 | 2023-04-04 | 上海贝美医药科技有限公司 | Preparation method of ticagrelor and intermediate thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101495444A (en) * | 2006-08-05 | 2009-07-29 | 阿斯利康(瑞典)有限公司 | A process for the preparation of optically active cyclopropylamines |
| CN101495442A (en) * | 2006-08-05 | 2009-07-29 | 阿斯利康(瑞典)有限公司 | Chemical process for preparation of aromatic cyclopropane esters and amides |
| WO2012001531A2 (en) * | 2010-06-30 | 2012-01-05 | Actavis Group Ptc Ehf | Novel processes for the preparation of phenylcyclopropylamine derivatives and use thereof for preparing ticagrelor |
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2013
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101495444A (en) * | 2006-08-05 | 2009-07-29 | 阿斯利康(瑞典)有限公司 | A process for the preparation of optically active cyclopropylamines |
| CN101495442A (en) * | 2006-08-05 | 2009-07-29 | 阿斯利康(瑞典)有限公司 | Chemical process for preparation of aromatic cyclopropane esters and amides |
| WO2012001531A2 (en) * | 2010-06-30 | 2012-01-05 | Actavis Group Ptc Ehf | Novel processes for the preparation of phenylcyclopropylamine derivatives and use thereof for preparing ticagrelor |
Non-Patent Citations (1)
| Title |
|---|
| 用 Sharpless 不对称双羟化反应合成手性 β-氨基醇;柳文敏 等;《有机化学》;20061231;第26卷(第3期);341-345 * |
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