CN107793420A - A kind of synthetic method of 3,4 dihydro 2H pyrans [3,2 b] pyridines - Google Patents

A kind of synthetic method of 3,4 dihydro 2H pyrans [3,2 b] pyridines Download PDF

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Publication number
CN107793420A
CN107793420A CN201711304716.0A CN201711304716A CN107793420A CN 107793420 A CN107793420 A CN 107793420A CN 201711304716 A CN201711304716 A CN 201711304716A CN 107793420 A CN107793420 A CN 107793420A
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pyrans
compound
synthetic method
dihydros
pyridine
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徐红岩
唐莅东
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Kang (shanghai) New Medicine Research & Development Co Ltd
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Kang (shanghai) New Medicine Research & Development Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to a kind of synthetic method of 3,4 dihydro 2H pyrans [3,2 b] pyridines.Raw material existing for mainly solving existing synthetic method is not easy to obtain, and reactions steps length, palladium chtalyst is hydrogenated with and taken off benzyl and uses precious metal palladium, and reclaims also difficult technical problem.The technical scheme is that：A kind of synthetic method of 3,4 dihydro 2H pyrans [3,2 b] pyridines, it is characterized in that comprising the following steps：The first step, 3 pyridones add iodine in aqueous sodium carbonate, obtain compound 1；Second step, in the presence of alkali compounds, compound 1 and 1, the reaction of 3 dibromopropanes, it is stirred overnight at room temperature, obtains compound 2；3rd step, at low temperature compound 2 and n-BuLi reacted in tetrahydrofuran, obtain target compound 3,4 dihydro 2H pyrans [3,2 b] pyridine.Product of the present invention is the important skeleton structure of synthetic drug.

Description

A kind of synthetic method of 3,4- dihydros -2H- pyrans [3,2-b] pyridine
Technical field
The present invention relates to 3,4- dihydros -2H- pyrans [3,2-b] pyridine synthesis, belong to pharmaceutical synthesis Chemical Engineering Technology neck Domain.
Background technology
Because pyridine ring has bioactivity, 3,4-dihydro-2H- pyrans [3,2-b] pyridine be synthetic drug important bone Frame structure, it can also easily be reduced to corresponding octahydro -2H- pyrans [3,2-b] and pyridine.Therefore in medical research To extensive use.
Patent WO 2013071697A1 disclose a kind of synthesis 3,4-dihydro-2H- pyrans [3,2-b] pyridine method, This method is using 3- pyridone -2- methanol as raw material, by benzyl selective protection phenolic hydroxyl group, manganese dioxide, Huo Na That-Wordsworth-Ai Mengsi reactions (Horner-Wadsworth-Emmons) reaction, palladium chtalyst are hydrogenated with and taken off benzyl, lithium aluminium hydride reduction Reduction, hydrobromic acid dehydration intramolecular cyclization.Because raw material is not easy to obtain, reactions steps length, palladium chtalyst is hydrogenated with and takes off your gold benzyl uses Belong to palladium, and reclaim also hardly possible.
Synthetic line is as follows:
The content of the invention
The purpose of the present invention is a kind of open low cost, high-efficient simple, quickly obtains 3,4- dihydros -2H- pyrans [3,2-b] The synthetic method of pyridine.Raw material existing for mainly solving existing synthetic method is not easy to obtain, and reactions steps length, palladium chtalyst is hydrogenated with and taken off Benzyl uses precious metal palladium, and reclaims also difficult technical problem.
The technical scheme is that：A kind of 3,4- dihydros -2H- pyrans [3,2-b] pyridine synthetic method, it is characterized in that Comprise the following steps：The first step, 3- pyridones add iodine in aqueous sodium carbonate, obtain compound 1；Second step, In the presence of alkali compounds, compound 1 and the reaction of 1,3- dibromopropane, it is stirred overnight at room temperature, obtains compound 2；3rd Step, compound 2 and n-BuLi react in tetrahydrofuran at low temperature, obtain target compound 3,4- dihydros -2H- pyrans [3,2-b] pyridine.
Synthetic line is as follows：
In above-mentioned reaction, second step alkali compounds is one kind in sodium carbonate, potassium carbonate or cesium carbonate, preferred potassium carbonate, institute State 2 equivalents that the amount that second step alkali compounds and 1,3- dibromopropanes add is the iodo- 3- pyridones of 2-；Low temperature described in 3rd step For -70~-90 DEG C, preferable reaction temperature is -78 DEG C.
The beneficial effects of the invention are as follows：Route is succinctly efficient, and agents useful for same is cheap, and reaction condition is simple, and reaction yield is high.
Embodiment
Embodiment 1：
The first step, 3- pyridones (20.0 g, 0.21 mol) and water (1600 mL) are added into three-necked flask；In room Temperature is lower to add sodium carbonate (46.4 g, 0.44 mol) and iodine (53.2 g, 0.21 mol), is stirred at room temperature 2 hours.With 1 N salt acid for adjusting pH=4, a large amount of solids separate out, filtering, dry compound 1 (41.9 g, 0.19 mol, 90 %).
1H NMR (400 MHz, DMSO-d 6 ): δ 10.87 (s, 1H), 7.84 (dd, J 1=1.6 Hz, J 2= 4.4 Hz, 1H), 7.21 (dd, J 1=4.4 Hz, J 2=8.0 Hz, 1H), 7.14 (dd, J 1=1.2 Hz, J 2=8.0 Hz, 1H)。
Second step, compound 1 (11.2 g, 50.7 mmol) and acetonitrile (150 mL) are added into three-necked flask. Potassium carbonate (14.1 g, 102.2 mmol) and 1,3- dibromopropane (20.5 g, 101.5 mmol), room temperature are added at room temperature It is stirred overnight.Filtering, filtrate are spin-dried for obtaining yellow oil.Column chromatography purify compound 2 (12.3 g, 36.0 mmol, 71 %)。
1H NMR (400 MHz, DMSO-d 6): δ 7.98 (dd, J 1=1.6 Hz, J 2=4.4 Hz, 1H), 7.41-7.34 (m, 2H), 4.19 (t, J=5.8 Hz, 2H), 3.75 (t, J=6.4 Hz, 2H), 2.32-2.25 (m, 2H)。
3rd step, compound 2 (8.1 g, 23.7 mmol), tetrahydrofuran (150 mL) are added into three-necked flask； The hexane solution of n-BuLi is added dropwise at -78 DEG C（2.5 M, 10.5 mL, 26.3 mmol）, after being added dropwise, under equality of temperature Stirring 1 hour.Reaction, ethyl acetate extraction (120 mL x 3) is quenched in saturated aqueous ammonium chloride;Organic phase merges, with full Washed with saline solution (150 mL), sodium sulphate is dried, filtering.Filtrate is spin-dried for obtaining crude product, and column chromatography purifies to obtain brown oil 3,4-dihydro-2H- pyrans [3,2-b] pyridine（2.7 g, 19.9 mmol, 84%）.1H NMR (400 MHz, DMSO-d 6): δ 8.18 (dd, J 1=1.2 Hz, J 2=4.4 Hz, 1H), 7.15-7.09 (m, 2H), 4.15 (t, J=5.2 Hz, 2H), 2.84 (t, J=6.4 Hz, 2H), 2.04-1.98 (m, 2H)。
Embodiment 2, second step alkali compounds are sodium carbonate, and low temperature described in the 3rd step is -60 DEG C, and remaining is the same as embodiment 1.
Embodiment 3, second step alkali compounds are cesium carbonate, and low temperature described in the 3rd step is -90 DEG C, and remaining is the same as embodiment 1.

Claims (5)

1. a kind of synthetic method of 3,4- dihydros -2H- pyrans [3,2-b] pyridine, it is characterized in that：Including lower step：The first step, 3- pyridones, with simple substance Iod R, obtain compound 1 in sodium bicarbonate aqueous solution；Second step, compound 1 and 1,3- bis- N-Propyl Bromide reacts in the presence of alkali compounds, is stirred overnight at room temperature, and obtains compound 2；3rd step, the He of compound 2 under low temperature N-BuLi reacts in tetrahydrofuran, obtains target compound 3,4- dihydros -2H- pyrans [3,2-b] pyridine, synthetic line is such as Under：
。
2. a kind of synthetic method of 3,4- dihydros -2H- pyrans [3,2-b] pyridine according to claim 1, it is characterized in that： The second step alkali compounds is one kind in sodium carbonate, potassium carbonate or cesium carbonate.
3. a kind of synthetic method method of 3,4- dihydros -2H- pyrans [3,2-b] pyridine according to claim 2, its feature It is：The second step alkali compounds is potassium carbonate.
4. a kind of synthetic method of 3,4- dihydros -2H- pyrans [3,2-b] pyridine according to claim 1, it is characterized in that The amount that the second step alkali compounds and 1,3- dibromopropanes add is 2 equivalents of the iodo- 3- pyridones of 2-.
5. a kind of synthetic method of 3,4- dihydros -2H- pyrans [3,2-b] pyridine according to claim 1, it is characterized in that Low temperature described in 3rd step is -70~-90 DEG C.
CN201711304716.0A 2017-12-11 2017-12-11 A kind of synthetic method of 3,4 dihydro 2H pyrans [3,2 b] pyridines Pending CN107793420A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112830933A (en) * 2021-02-04 2021-05-25 康化（上海）新药研发有限公司 Synthetic method of 3, 4-dihydro-2H-pyrano [2,3-b ] pyridine

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CN103102344A (en) * 2011-11-14 2013-05-15 广东东阳光药业有限公司 Aminoquinazoline derivative, salts thereof and application method
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CN103102344A (en) * 2011-11-14 2013-05-15 广东东阳光药业有限公司 Aminoquinazoline derivative, salts thereof and application method
CN102516253A (en) * 2011-12-27 2012-06-27 盛世泰科生物医药技术(苏州)有限公司 Method for synthesizing 3,4-dihydro-2H-pyrano[3,2-b]pyridine
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112830933A (en) * 2021-02-04 2021-05-25 康化（上海）新药研发有限公司 Synthetic method of 3, 4-dihydro-2H-pyrano [2,3-b ] pyridine

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Application publication date: 20180313