CN103073525A - Method for synthesizing (S)-(3,4-difluorophenyl)hexamethylene oxide - Google Patents

Method for synthesizing (S)-(3,4-difluorophenyl)hexamethylene oxide Download PDF

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CN103073525A
CN103073525A CN2013100439828A CN201310043982A CN103073525A CN 103073525 A CN103073525 A CN 103073525A CN 2013100439828 A CN2013100439828 A CN 2013100439828A CN 201310043982 A CN201310043982 A CN 201310043982A CN 103073525 A CN103073525 A CN 103073525A
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difluorophenyl
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CN103073525B (en
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杨运旭
王爱志
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University of Science and Technology Beijing USTB
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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

The method of a kind of synthetic preparation (S)-(3,4-difluorophenyl) epoxy hexane
Technical field:
The invention belongs to the pharmaceutical chemistry field, the particularly synthetic preparation of a kind of chirality ( S)-(3,4-difluorophenyl) method of oxyethane intermediate.This chiral intermediate is ADZ6140 required crucial chiral raw material when synthetic.
Background technology:
ADZ6140 (ticagrelon) (as shown in Equation 1) is a kind of selectivity small molecules anticoagulation medicine.Act on P2Y with being reversibility 12Acceptor, the platelet aggregation that adenosine diphosphate (ADP) (ADP) is caused has stronger restraining effect, and oral rear rapid onset, can obviously improve the symptom of acute coronary.When making up 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.Synthetic can the use of this cyclopropylamine building block ( S)-3,4-difluorophenyl oxyethane is the chirality starting raw material.
Figure 479962DEST_PATH_IMAGE001
Formula (1)
Figure 397102DEST_PATH_IMAGE002
Formula (2)
Existing document [1] report, through ( S)-3,4 two-fluorophenyl oxyethane intermediate, synthesized ( 1R, 2S)-2-(3, the 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 take the prochiral ketone precursor as raw material, through the reduction of prochiral ketone precursor, generates the chiral alcohol derivative in the presence of the chiral induction agent, becomes ring to generate the chiral epoxy compound again.The chiral epoxy compound that generates, Cyclopropanated through Wadsworth-Emmons, generate the chiral cyclopropane sulfonamide derivatives, namely ( 1R, 2S)-2-(3, the 4-difluorophenyl) cyclopropylamine.These method routes are brief, and more direct when making up chiral centre, the optical purity of chiral material is higher.Its route method is as seeing accompanying drawing 1.
But, above-mentioned document synthetic ( S)-2-chloro-1-(3,4-difluorophenyl) during ethanol, still need use BH 3-Me 2The S 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 take it as chiral raw material, can synthesize the chiral intermediate building block (1R of ADZ6140 key under the condition easy, that reaction conditions is gentle, with low cost, 2S)-and 2-(3, the 4-difluorophenyl) cyclopropylamine.
The present invention's proposition ( SThe synthetic method route of)-3,4 difluorophenyl oxyethane is seen accompanying drawing 2.
A kind of synthetic preparation (S)-3, the method for 4-fluorophenyl epoxy hexane is characterized in that synthesis step is as follows:
(1) in the presence of Toluidrin, with T-BuOH/H 2O is solvent, and AD-mix-α is oxygenant, and 3,4-difluorobenzene ethene is carried out the AD reaction of Sharpless, generate ( S)-(3, the 4-difluorophenyl) ethylene glycol;
(2) incite somebody to action ( S)-(3, the 4-difluorophenyl) ethylene glycol " one kettle way " and triethly orthoacetate mixing, after the reaction condensation, get the ring-shaped condensate intermediate under the certain temperature;
(3) this ring-type shape condenses intermediate and bromide reagent are mixed, reaction adds entry after finishing, and tells organic layer, the treated bromo-derivative intermediate that gets;
(4) step (3) gained bromide intermediate is in organic solvent, reacting by heating in the presence of Anhydrous potassium carbonate, namely get ( S)-(3, the 4-difluorophenyl) oxyethane.
Further, in the described step (2), be with ( S)-(3,4-difluorophenyl) ethylene glycol at first mixes 10 ℃ with triethly orthoacetate--100 ℃ of lower reactions, after the reaction condensation, steam except excessive triethly orthoacetate, and get the ring-shaped condensate intermediate.
Further, described step (3) temperature of reaction is 10 ℃--100 ℃.
Further, described step (3) bromide reagent is acetyl bromide or bromotrimethylsilane.
Further, in the described step (4), used organic solvent is methyl alcohol, ethanol, acetonitrile polar solvent.
The invention has the advantages that: reactions steps is short, and reaction conditions is gentle, and the products therefrom optical purity is high.
Description of drawings
Fig. 1 be background technology Literature [1] ( S)-3,4-difluorophenyl ethylene oxide synthesis route map.
Fig. 2 is method synthetic route chart of the present invention.
Embodiment:
Embodiment 1:
(1) in reaction vessel, puts into T-BuOH/H 2O(10ml, v/v=1:1), AD-mix-α (2.0g), mix and blend added Toluidrin (158mg, 1.66mmol) after 15 minutes, and restir adds after 15 minutes under 3,4-difluorobenzene ethene (193mg, the 1.38mmol) room temperature and stirred 24 hours.Add S-WAT 2.0g, continue to stir 1 hour, reaction mixture water (30ml) is processed, CH 2Cl 2Extraction (3 * 50ml), merge organic phase, dried over mgso.After removal of solvent under reduced pressure, get 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) with (24.7g, 0.142mol) ( S)-(3, the 4-difluorophenyl) ethylene glycol, the 70ml methylene dichloride drops in the there-necked flask, and stirring and dissolving is warming up to 50 ℃, adds 25.27 gram triethly orthoacetates, reacts after one hour, and termination reaction steams low-boiling point material, gets ring-shaped condensate intermediate 34 grams.Without purifying, be directly used in the next step, yield 100%.
Above-mentioned ring-shaped condensate intermediate 34 grams are dissolved in the 50ml methylene dichloride, after adding acetyl bromide 19.18 gram reaction 2h, in system, add 70ml water termination reaction, collected organic layer, water layer is used the dichloromethane extraction secondary again, dried over mgso, decompression get viscous material 35.6 grams, yield 90% after removing methylene dichloride.It is bromo-derivative.
Above-mentioned bromo-derivative 35.6 grams, 70ml methyl alcohol, Anhydrous potassium carbonate, back flow reaction 1h, finish reaction after, decompression steams methyl alcohol, resistates is dissolved in the 70ml methylene dichloride, adds 30ml water, washes twice.Organic layer adds dried over mgso.Decompression steams methylene dichloride.70-73 degree fraction/10mmHg is collected under reduced pressure distillation, gets product 17.7 grams, yield 80%, namely ( S)-(3, the 4-difluorophenyl) oxyethane.
Embodiment 2:
(1) in reaction vessel, puts into T-BuOH/H 2O(5ml, v/v=1:1), AD-mix-α (1.0g),
Behind the mix and blend 15 minutes, add Toluidrin (79mg, 0.83mmol), restir adds after 15 minutes under 3,4-difluorobenzene ethene (96.5mg, the 0.69mmol) room temperature and stirred 24 hours.Add S-WAT 1.0g, continue to stir 1 hour, reaction mixture water (15ml) is processed, CH 2Cl 2Extraction (3 * 50ml), merge organic phase, dried over mgso.After removal of solvent under reduced pressure, get 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) with (12.4g, 0.071mol) ( S)-(3, the 4-difluorophenyl) ethylene glycol, the 35ml methylene dichloride drops in the there-necked flask, and stirring and dissolving is warming up to 50 ℃, adds 12.64 gram triethly orthoacetates, reacts after one hour, and termination reaction steams low-boiling point material, gets ring-shaped condensate intermediate 17 grams.Without purifying, be directly used in the next step, yield 100%.
Above-mentioned ring-shaped condensate intermediate 17 grams are dissolved in the 50ml methylene dichloride, after adding bromotrimethylsilane 10.86 gram reaction 2h, in system, add 35ml water termination reaction, collected organic layer, water layer is used the dichloromethane extraction secondary again, dried over mgso, decompression get viscous material 17.8 grams, yield 90% after removing methylene dichloride.It is bromo-derivative.
Above-mentioned bromo-derivative 17.8 grams, 35ml ethanol, Anhydrous potassium carbonate, back flow reaction 1h, finish reaction after, decompression steams ethanol, resistates is dissolved in the 35ml methylene dichloride, adds 15ml water, washes twice.Organic layer adds dried over mgso.Decompression steams methylene dichloride.72-75 degree fraction/10mmHg is collected under reduced pressure distillation, gets product 8.9 grams, yield 80%, namely ( S)-(3, the 4-difluorophenyl) oxyethane.

Claims (5)

  1. A 1. synthetic preparation ( S)-(3,4-difluorophenyl) method of epoxy hexane is characterized in that synthesis step is as follows:
    (1) in the presence of Toluidrin, with T-BuOH/H 2O is solvent, and AD-mix-α is oxygenant, and 3,4-difluorobenzene ethene is carried out the AD reaction of Sharpless, generate ( S)-(3, the 4-difluorophenyl) ethylene glycol;
    (2) incite somebody to action ( S)-(3, the 4-difluorophenyl) ethylene glycol " one kettle way " and triethly orthoacetate mixing, after the reaction condensation, get the ring-shaped condensate intermediate under the certain temperature;
    (3) this ring-type shape condenses intermediate and bromide reagent are mixed, reaction adds entry after finishing, and tells organic layer, the treated bromo-derivative intermediate that gets;
    (4) step (3) gained bromide intermediate is in organic solvent, reacting by heating in the presence of Anhydrous potassium carbonate, namely get ( S)-(3, the 4-difluorophenyl) oxyethane.
  2. 2. according to right 1 described method, it is characterized in that: in the described step (2), be with ( S)-(3,4-difluorophenyl) ethylene glycol at first mixes 10 ℃ with triethly orthoacetate--100 ℃ of lower reactions, after the reaction condensation, steam except excessive triethly orthoacetate, and get the ring-shaped condensate intermediate.
  3. 3. according to right 1 described method, it is characterized in that: described step (3) temperature of reaction is 10 ℃--100 ℃.
  4. 4. according to right 1 described method, it is characterized in that: described step (3) bromide reagent is acetyl bromide or bromotrimethylsilane.
  5. 5. according to right 1 described method, it is characterized in that: in the described step (4), used organic solvent is methyl alcohol, ethanol, acetonitrile polar solvent.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008018822A1 (en) * 2006-08-05 2008-02-14 Astrazeneca Ab Chemical process for preparation of aromatic cyclopropane esters and amides
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
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008018822A1 (en) * 2006-08-05 2008-02-14 Astrazeneca Ab Chemical process for preparation of aromatic cyclopropane esters and amides
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
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
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)

* Cited by examiner, † Cited by third party
Title
柳文敏 等: "用 Sharpless 不对称双羟化反应合成手性 β-氨基醇", 《有机化学》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

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