CN106928136A - A kind of Graphene palladium cobalt sequential catalyst synthesizes the method for MK intermediate - Google Patents

A kind of Graphene palladium cobalt sequential catalyst synthesizes the method for MK intermediate Download PDF

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CN106928136A
CN106928136A CN201710099701.9A CN201710099701A CN106928136A CN 106928136 A CN106928136 A CN 106928136A CN 201710099701 A CN201710099701 A CN 201710099701A CN 106928136 A CN106928136 A CN 106928136A
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vinyl
phenyl
chloro
hydroxypropyls
methyl benzoate
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CN106928136B (en
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高令峰
郑庚修
韩歆雨
付凯
王秋芬
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University of Jinan
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Quinoline Compounds (AREA)
  • Catalysts (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a kind of technique of chemical synthetic drug intermediate, the more particularly to Graphene palladium cobalt sequential catalyst synthetic method of MK intermediate [S (E)] 2 [3 [3 [2 (quinolyl of 7 chlorine 2) vinyl] phenyl] 3 hydroxypropyls] methyl benzoate, the method is using coupling, two step one kettle way sequential catalyst systems of reduction, intermediate product is not required to separate, it is simple to operate, yield is high, chiral selectivity is good, is applicable to industrialized production.

Description

A kind of Graphene palladium cobalt sequential catalyst synthesizes the method for MK intermediate
Technical field
The invention belongs to medical chemistry synthesis field, and in particular to a kind of synthetic route side of MK intermediate Method.
Background technology
Menglusitena (Montrlukast Sodium) it is chemical entitled：2- (1- ((1 (R)-(3- (2- (the chloro- 2- quinolines of 7- Quinoline base)-(E)-vinyl) phenyl) -3- (2- (propyl group of 2- hydroxyls -2) phenyl)-rosickyite base) methyl) cyclopropyl) sodium acetate, use Make Zhichuan agent, anti-allergic agent etc..Exploitation is synthesized by Canadian Merk-Frosst companies first, the said firm is in Chinese patent Structure of the compound and preparation method thereof is disclosed in CN1061407A, wherein by 1- (S)-(3- (2- (7- chloroquinolines -2- Base)-(E)-vinyl) phenyl) after the protection of -3- (2- (2- hydroxyl -2- propyl group) phenyl) propyl alcohol chosen property, then with 2- (1- (mercaptos Methyl) cyclopropyl) sulfydryl on methyl acetate carries out nucleophilic displacement of fluorine, and further hydrolyze, obtain MK into salt.It is closed It is shown below into route.
Chinese patent CN1428335A discloses the synthetic method of another Menglusitena, with 2- (3- (3- (2- (7- Chloro- 2 quinolyl)-(E)-vinyl) phenyl)-(3R)-hydroxypropyl) methyl benzoate be raw material, hydroxyl is converted into sulfonic acid Ester leaving group, then with thiacetate and the hydroxyl reaction of 3, obtain 2- (3- (3- (2- (chloro- 2 quinolyls of 7-)-(E)-second Alkenyl) phenyl)-(3R)-(acetyl mercapto) propyl group) methyl benzoate.Added using methyl Grignard para Toluic Acid's methyl esters Into the tertiary alcohol is obtained, while thiacetate can in the basic conditions be hydrolyzed into mercaptoalcohol.The sulfydryl tertiary alcohol again with 2- (1- bromomethyls) Cyclopropaneacetic acid ester reacts, and obtains 2- (1- ((1 (R)-(3- (2- (the chloro- 2- quinolyls of 7-)-(E)-vinyl) phenyl) -3- (2- (2- hydroxyl -2- propyl group) phenyl) rosickyite base) methyl) cyclopropyl) acetic acid esters, 2- (1- bromomethyls) cyclopropaneacetic acid ester is in alkalescence Under can hydrolyze and obtain cyclopropaneacetic acid, further with NaOH neutralization reaction, obtain target compound Menglusitena.Its Synthetic route is shown below.
As coupling reaction is furtherd investigate, the industrial applications of coupling reaction become more and more extensively, Brian in 2004 M. Stoltz groups report using the chiral propyl alcohol raw material 7a of S configurations, by raw material 7a on Adv. Synth. Catal. The bromine and 2- vinyl -7- chloroquinolines of 3 on double bond coupling direct construction trans double bond so that quinoline ring and chirality third The efficient coupling of raw polyol is completed.In this article, author have also been developed a kind of method of new synthesis of chiral propyl alcohol, main If by the thinking of such as following formula, the alcohol for aoxidizing R configurations by the chiral selectivity of palladium chtalyst is converted into ketone carbonyl, so that S The alcohol of configuration is separated, then by ketone carbonyl be reduced into alcohol after re-use, chiral alcohol can be obtained with efficient.This The chiral separation method of sample shows value higher in terms of the chiral raw material recovery of high price.Its synthetic route such as following formula It is shown.
2001, Hashiguchi groups reported chiral using ruthenium on Journal of Organic Chemistry 8a ketone carbonyls, can be reduced into alcohol by the restoring method of catalyst, and product ee values can reach 92%.But this catalyst needs High rhodium and chiral ligand, the synthesis cost of catalyst and the synthesis difficulty of chiral ligand are all than larger, and product alcohol ee Value can only achieve 92%.Its synthetic route is shown below.
In summary it is described, either most traditional linear synthetic route method, then by the fractionation of chiral selectors Obtain chiral alcohol；Or molecular framework is built by coupling reaction, and uses the catalysis of chiral catalyst to select to split, all very Clearly point out, the synthesis of chiral alcohol is the committed step in MK synthesis, the quick of chiral raw polyol is blended into pass It is important.The method for finding research synthesis of chiral alcohol intermediate, the more synthetically prepared MK intermediate hand of quickness and high efficiency Property alcohol intermediate be very important basic research direction, be also beneficial to create bigger economic society value.
The content of the invention
Present invention mainly solves technical problem, be to provide a kind of route methods of the step cascade reaction of one kettle way two, be not required to The separation of intermediate product ketone, directly obtains the Montelukast intermediate of chiral control（III）[S-(E)]-2-[3-[3-[2-(7- Chloro- 2- quinolyls) vinyl] phenyl] -3- hydroxypropyls] methyl benzoate, wherein main reaction by Heck is obtained in the middle of ketone Body, is not required to separate change reaction condition, adds chiral ligand, then adds reducing agent, after control condition reaction terminates, passes through After filter, extraction, column chromatography for separation, you can obtain Montelukast intermediate [S- (E)] -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) Vinyl] phenyl] -3- hydroxypropyls] methyl benzoate.It is specific as follows：
1st, a kind of MK intermediate [S- (E)] -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] phenyl] -3- hydroxyls Base propyl group] methyl benzoate（III）Graphene palladium cobalt sequential catalyst synthetic method, according to the synthetic route as shown in formula.
2nd, a kind of Meng Lusi sodium intermediate（III）[S- (E)] -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] benzene Base] -3- hydroxypropyls] methyl benzoate Graphene palladium cobalt sequential catalyst synthetic method,（a）Coupling reaction synthetic intermediate II 80 ~ 120o8 ~ 14 hours, preferably 85 ~ 110 are reacted under CoC reacts 8 ~ 12 hours；Reaction terminate rear reacting liquid temperature- 10~0oUnder C, preferably -5 ~ 0oC；To ligand L is added in reaction solution, stirred 20 ~ 30 minutes after adding ligand L, control reaction solution Temperature is 0 ~ 5oC is dividedly in some parts sodium borohydride, then controls reacting liquid temperature 15 ~ 20oReacted 3 ~ 5 hours under C, after reaction terminates, control Reacting liquid temperature processed is 0 ~ 5oC, adds saturated aqueous ammonium chloride that reaction is quenched；（b）Palladium Co catalysts are filtered to remove, then are passed through Extraction, dries, and revolving, column chromatography for separation obtains Meng Lusi sodium intermediate [S- (E)] -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) Vinyl] phenyl] -3- hydroxypropyls] methyl benzoate.
3rd, a kind of Montelukast intermediate（III）[S- (E)] -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] benzene Base] -3- hydroxypropyls] methyl benzoate Graphene palladium Co catalysts sequential catalyst method and step, solvent be anhydrous N, N- bis- NMF, anhydrous DMA, anhydrous dimethyl sulfoxide, preferably DMF, anhydrous N, N- Dimethylacetylamide.
4th, a kind of Montelukast intermediate（III）[S- (E)] -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] benzene Base] -3- hydroxypropyls] methyl benzoate Graphene palladium Co catalysts sequential catalyst method,（a）In step, add ligand L with The mol ratio of palladium is 1 in Graphene palladium Co catalysts:1 ~ 1.4, preferably 1:1~1.2；The compound of raw material such as Formulas I：BY3Rub That ratio=1:1.5 ~ 3.0, preferably 1:1.5~2.5；The compound of raw material such as Formulas I：Sodium borohydride mol ratio=1:2.0 ~ 3.0, it is excellent Elect 1 as:2.0~2.6.
A kind of Graphene palladium cobalt catalysis series connection prepares Montelukast intermediate [S- (E)] -2- [3- [3- [2- (chloro- 2- quinolines of 7- Quinoline base) vinyl] phenyl] -3- hydroxypropyls] methyl benzoate（III）Synthetic method, the Graphene palladium cobalt being filtrated to get urges Agent, washs, 50 through water, ethanoloReusable three times after C vacuum drying.
Beneficial effect of the present invention：In the middle of the MK chiral alcohol that one pot of series connection two-step reaction synthesis of the invention is obtained Body, yield is up to 99.5% up to 76.1%, ee, reaches the chiral requirement of pharmaceutical intermediate, and heterogeneous graphene-supported Reusable three times of palladium Co catalysts, yield, selectivity still have preferable effect.
Specific implementation case
Example 1, [S- (E)] -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] phenyl] -3- hydroxypropyls] methyl benzoate Synthesis：
The first step：Take addition 300mg (E) -1- (3- (2- (7- in the three neck round bottom flask of a dry 100mL Chloroquinolin-2-yl) vinyl) phenyl) prop-2-en-1-ol, 200mg o-bromobenzoic acid methyl esters, 20mg is containing palladium The graphene-supported palladium cobalt Nano capsule of 10% mass fraction, nitrogen protection is lower to add 20 milliliters of anhydrous DMFs, Then 1.7mL diisopropylamines, 95 is added dropwiseoReacted 10 hours under C, monitoring raw material (E) -1- (3- (2- (7- Chloroquinolin-2-yl) vinyl) phenyl) after prop-2-en-1-ol reacts completely, stop reaction, reaction solution from So it is cooled to room temperature；Control the anhydrous and oxygen-free environment of reaction system.
Second step：Keep the N of reaction system2Protection, under ice-water bath cooling, control reacting liquid temperature is in 2-5oC, in reaction solution Add ligand 1 7.1mg (1S, 2S)-N- (2- (tert-butyl) -6- (di-4-methyl-phenylphosphanyl) benzyl)-2-((2-(tert-butyl)-6-(di-4-methyl-phenylphosphanyl)benzyl)-λ2-azanyl) Cyclohexan-1-amine, stirring reaction 20 minutes, then adds 254mg australenes（alpha-pinene）, syringe 0.18mL BBr are added dropwise3, 100mg sodium borohydrides are then dividedly in some parts, after adding, heat up 15 ~ 20oUnder C, 3.5 hours are reacted extremely After the complete reduction reaction of intermediate product ketone, it is 0 that then ice salt bath is cooled to reacting liquid temperatureoC, is added dropwise saturated ammonium chloride water-soluble Liquid is quenched reaction, is filtered to remove palladium Co catalysts, is then extracted at twice with 200mL ethyl acetate, merges organic phase, uses saturation Salt solution (3 × 50 mL) is washed, anhydrous sodium sulfate drying 1 hour, filtering, is spin-dried for rear solid and is obtained Meng through column chromatography for separation This sodium intermediate of Shandong（III）[S- (E)] -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] phenyl] -3- hydroxypropyls] benzene Methyl formate 318.5mg, yield 76.1%, 99.5%ee.
Specific embodiment 2：[S- (E)] -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] phenyl] -3- hydroxyls third Base] methyl benzoate synthesis：The first step：Take addition 680mg (E) -1- in the three neck round bottom flask of dry 100 mL (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) prop-2-en-1-ol, 560mg o-bromobenzoic acid methyl esters, Graphene-supported palladium cobalt Nano capsules of the 50mg containing the mass fraction of palladium 10%, nitrogen protection is lower to add 30 mL anhydrous isopropyl alcohols, so 3.9mL diisopropylamines, 110 are added dropwise afterwardsoReacted 12 hours under C, monitoring raw material (E) -1- (3- (2- (7-chloroquinolin- 2-yl) vinyl) phenyl) after prop-2-en-1-ol reacts completely, stop reaction, reaction solution naturally cools to room temperature；Must The anhydrous and oxygen-free environment of reaction system must be controlled.
Second step：Keep the N of reaction system2Protection, under ice-water bath cooling, control reacting liquid temperature is 2 ~ 5oC, in reaction solution Add part 39.6mg (1S, 2S)-N- (2- (tert-butyl) -6- (di-4-methyl-phenylphosphanyl) benzyl)-2-((2-(tert-butyl)-6-(di-4-methyl-phenylphosphanyl) benzyl) -λ2- Azanyl) cyclohexan-1-amine, stirring reaction 25 minutes, then adds 660.4mg australenes（alpha- pinene）, syringe dropwise addition 0.18mL BBr3, 250.1mg sodium borohydrides are then dividedly in some parts, after adding, heat up, 15 ~ 20oUnder C, to after the complete reduction reaction of intermediate product ketone, it is 0 that then ice salt bath is cooled to reacting liquid temperature within 4 hours for reactionoC, drop Plus saturated aqueous ammonium chloride is quenched reaction, palladium Co catalysts are filtered to remove, are then extracted in three times with 400mL ethyl acetate, Merge organic phase, washed with saturated brine (3 × 80 mL), anhydrous sodium sulfate drying 1 hour, filter, be spin-dried for rear solid through post Chromatography is to obtain Meng Lusi sodium intermediates（III）[S- (E)] -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] benzene Base] -3- hydroxypropyls] methyl benzoate 674mg, yield 72.1%, 99.1%ee.
Specific embodiment 3：[S- (E)] -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] phenyl] -3- hydroxyls third Base] methyl benzoate synthesis：The first step：682 mg (E) -1- is added in the three neck round bottom flask for taking dry 100 mL (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) prop-2-en-1-ol, 565 mg o-bromobenzoic acid first Ester, 54 mg are recovered by filtration the graphene-supported palladium cobalt nanocatalyst for being reclaimed through water, ethanol washing again, and nitrogen protection is lower to be added 30 mL anhydrous isopropyl alcohols, are then added dropwise 3.9mL diisopropylamines, 110oReacted 12 hours under C, monitoring raw material (E) -1- (3- (2- (7-chloroquinolin-2-yl) vinyl) phenyl) after prop-2-en-1-ol reacts completely, stop reaction, reaction solution Naturally cool to room temperature；The anhydrous and oxygen-free environment of reaction system must be controlled.
Second step：Keep the N of reaction system2Protection, under ice-water bath cooling, control reacting liquid temperature is 2 ~ 5oC, in reaction solution Add part 39.3mg (1S, 2S)-N- (2- (tert-butyl) -6- (di-4-methyl-phenylphosphanyl) benzyl)-2-((2-(tert-butyl)-6-(di-4-methyl-phenylphosphanyl) benzyl) -λ2- Azanyl) cyclohexan-1-amine, stirring reaction 25 minutes, then adds 660.4mg australenes（alpha- pinene）, syringe dropwise addition 0.18mL BBr3, 250.8 mg sodium borohydrides are then dividedly in some parts, after adding, heat up, 15 ~ 20oUnder C, to after the complete reduction reaction of intermediate product ketone, it is 0 that then ice salt bath is cooled to reacting liquid temperature within 4 hours for reactionoC, drop Plus saturated aqueous ammonium chloride is quenched reaction, palladium Co catalysts are filtered to remove, are then extracted in three times with 400mL ethyl acetate, Merge organic phase, washed with saturated brine (3 × 80 mL), anhydrous sodium sulfate drying 1 hour, filter, be spin-dried for rear solid through post Chromatography is to obtain Meng Lusi sodium intermediates（III）[S- (E)] -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] benzene Base] -3- hydroxypropyls] methyl benzoate 671mg, yield 72.0%, 99.1%ee.
Although above-mentioned be described to specific embodiment of the invention in conjunction with the embodiments, not the present invention is implemented The restriction of mode.For one of ordinary skill in the art, on the basis of technical scheme, those skilled in the art are not Need the various modifications made by paying creative work or deformation still within protection scope of the present invention.

Claims (5)

1. a kind of Graphene palladium cobalt catalysis series connection prepares MK intermediate [S- (E)] -2- [3- [3- [2- (chloro- 2- quinolines of 7- Quinoline base) vinyl] phenyl] -3- hydroxypropyls] methyl benzoate（III）Synthetic method, it is characterised in that according to such as formula institute The synthetic route shown：。
2. a kind of Graphene palladium cobalt catalysis series connection according to claim 1 prepares [S- (E)] -2- [[[(7- is chloro- for 2- for 3- for 3- 2- quinolyls) vinyl] phenyl] -3- hydroxypropyls] methyl benzoate（III）Synthetic method, it is characterised in that：
（a）Coupling reaction synthetic intermediate II is 80 ~ 120oReacted 8 ~ 14 hours under C；React cooling -10 ~ 0 after terminatingoC, to Ligand L is added in reaction solution, is stirred 20 ~ 30 minutes after adding ligand L, control reacting liquid temperature is 0 ~ 5oC is dividedly in some parts boron hydrogen Change sodium, then control reacting liquid temperature 15 ~ 20oReacted 3 ~ 5 hours under C, after reaction terminates, control reacting liquid temperature is 0 ~ 5oC, plus Enter saturated aqueous ammonium chloride and reaction is quenched；
B () is filtered to remove Graphene palladium Co catalysts, then through extraction, dry, and revolving, column chromatography for separation is obtained in the middle of Meng Lusi sodium Body [S- (E)] -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] phenyl] -3- hydroxypropyls] methyl benzoate.
3. a kind of Graphene palladium cobalt catalysis series connection prepares Montelukast intermediate [S- (E)] -2- [3- according to claim 1 [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] phenyl] -3- hydroxypropyls] methyl benzoate（III）Synthetic method, its feature It is that solvent is DMF, DMA, dimethyl sulfoxide (DMSO).
4. a kind of Graphene palladium cobalt catalysis series connection prepares Montelukast intermediate [S- (E)] -2- [3- according to claim 1 [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] phenyl] -3- hydroxypropyls] methyl benzoate（III）Synthetic method, its feature It is,（a）In step, ligand L is 1 with the mol ratio of palladium in Graphene palladium Co catalysts:1 ~ 1.4, the chemical combination of raw material such as Formulas I Thing：BY3：Mol ratio=1 of sodium borohydride:1.5~3.0:2.0~3.0.
5. a kind of Graphene palladium cobalt catalysis series connection prepares Montelukast intermediate [S- (E)] -2- [3- according to claim 1 [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] phenyl] -3- hydroxypropyls] methyl benzoate（III）Synthetic method, its feature It is the Graphene palladium Co catalysts being filtrated to get, is washed through water, ethanol, 50oReusable three times after C vacuum drying.
CN201710099701.9A 2017-02-23 2017-02-23 A kind of method of graphene palladium cobalt sequential catalyst synthesis montestron sodium intermediate Expired - Fee Related CN106928136B (en)

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