CN102101861B - Synthesis and process method of nitrogen-containing bis-heterocyclic medicine intermediate - Google Patents
Synthesis and process method of nitrogen-containing bis-heterocyclic medicine intermediate Download PDFInfo
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- CN102101861B CN102101861B CN2011100660224A CN201110066022A CN102101861B CN 102101861 B CN102101861 B CN 102101861B CN 2011100660224 A CN2011100660224 A CN 2011100660224A CN 201110066022 A CN201110066022 A CN 201110066022A CN 102101861 B CN102101861 B CN 102101861B
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Abstract
The invention provides a synthesis and process method of a novel quinolinone carboxylic acid and naphthyridinone carboxylic acid antibacterial medicament intermediate multi-nitrogen heterocycle for treating prostatoplasia and the like. A nitrogen-containing bis-heterocyclic compound is obtained from cheap and readily-available pyridine dicarboxylic acid serving as a raw material by a reaction consisting of four steps. The method has the advantages of readily available raw materials, low cost, simple reaction, easiness in controlling, treating and expanding production and high yield, and comprises but is not limited to aliphatics, aromatic series and heterocyclic multi-nitrogen heterocycles. The invention provides a practical synthesis and process method of a quinolinone carboxylic acid and naphthyridinone carboxylic acid medicament intermediates for environmentally-friendly chemical industry.
Description
Division explanation: the dividing an application of audit opinion proposition of " the synthetic and process method of novel polynitrogen heterocycle pharmaceutical midbody " (application number 200810043577.5) apply in application of the present invention on July 1st, 2008 to the scientific and technological (Shanghai) Co., Ltd. of splendid chemistry far away according to State Intellectual Property Office's notification of examiner's opinion (dispatch sequence number 2010112500608890).Except that this case " the synthetic and process method of nitrogenous pair of heterocycle medicine intermediate "; New division has " the synthetic and process method of polynitrogen heterocycle pharmaceutical midbody ", " the synthetic and process method of azabicyclo medicine intermediate "; Keep July 1 2008 preferential date, and application is open in advance and examination as to substances.
I. background is summarized
Polynitrogen heterocycle becomes newtype drug (US5202337, US5071999, US20050234031, US5179090, US5468742 in recent years; US 20050101602, US20050197333, US6114531, US5298629, US2004242641; TL46 (42), 2005,7179-7200, US5654318, JMC36 (16); 1993,2311-2320, WO2004/832) important midbody, this type of compound is synthetic to cause extensive interest, is the Recent study focus.General synthetic route is longer, the loaded down with trivial details difficulty of aftertreatment, raw materials cost high be difficult to obtain, the three wastes are many, pollute big.Therefore the scientific research personnel is still constantly seeking more simple and easy and lower-cost compound method.
The purpose of this invention is to provide one begins through synthetic, process method than the synthetic polynitrogen heterocycle newtype drug midbody of short-circuit line from the raw material that simply is easy to get.Present method raw material is easy to get, and cost is lower, and the three wastes are few, handles simply, and yield is high, and is easy to suitability for industrialized production.
II. main contents of the present invention
The present invention relates to the synthetic and process method of nitrogenous pair of heterocyclic of one type of medicine intermediate, its molecular formula is shown in the following figure.Method synthetic route of the present invention is short, and raw material is easy to get, and is easy to purifying, and cost is low, is easy to industriallization.
Wherein R1 is methyl, hydrogen, phenyl, is preferably hydrogen, methyl; R2 is methyl, hydrogen, phenyl, is preferably hydrogen, methyl; R3 is hydrogen, alkyl, aryl, heterocyclic radical, is preferably hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl, isobutyl-, benzyl, phenyl, substituted-phenyl, pyridyl, substituted pyridinyl, thienyl; R4 is hydrogen, alkyl, aryl, heterocyclic radical, is preferably hydrogen, methyl, ethyl, sec.-propyl, benzyl, phenyl, pyridyl, thienyl; M=1-3 is preferably 1 and 2; N=1,2; P=0,1.
For helping further to understand the present invention, the structural formula of this compounds can further be expressed as structural formula (III) [m=2, n=p=1].
R wherein
3Be hydrogen, alkyl, aryl, heterocyclic radical, be preferably hydrogen, methyl, ethyl, sec.-propyl, cyclopropyl, isobutyl-, benzyl, phenyl, substituted-phenyl, pyridyl, substituted pyridinyl, thienyl.
Typical compound method reaction formula of the present invention is as follows, but does not limit content of the present invention.
Synthetic route is following:
The synthetic method can further describe as follows:
The first step pyridine dicarboxylic acid and benzylamine reaction make lactan; Second step lactan and the haloalkane react pyridinium salt; Lactan and haloalkane mol ratio 1: 3 were recommended mol ratio 1: 1.2, and recommending solvent for use is little polar solvents such as benzene,toluene,xylene; The 3rd step reduction pyridine ring, the recommendation catalyzer is Pd/C, Pd (OH)
2/ C, Rh/C or the like, recommended pressure 1-50kg/cm
2, temperature of reaction 20-100 degree, the 4th step was reduced into amine with lithium aluminium hydride with lactan, carbonyl compound and lithium aluminium hydride mol ratio 1: 6, recommending mol ratio is 1: 3.
Synthetic route method reaction temperature of the present invention with, be easy to control, be easy to amplify to produce, raw material is easy to get, productive rate is high, purifying products is simple.
III. invent instance
To help further to understand the present invention through following instance; They are merely for example, and practical ranges is not limited by instance.
Exemplary construction formula (III) compounds 3-methyl-3,8-diazabicyclo [4.3.0] nonane class synthetic
The first step
At room temperature, with the acetic anhydride of 170mL be added to 100g (0.6mol, 1eq) 3, in the 4-pyridine dicarboxylic acid; After dropwising, be heated to 110 degree, stirred 4 hours; Be cooled to room temperature, dense the doing of reducing pressure, the ether of 200mL joined in residual night; Filter, filter cake gets the acid anhydrides of 86g with ether washing (4*100).(0.7mol in benzylamine 1.17eq), is heated to 180 degree and stirred 30 minutes under cooling, acid anhydrides to be joined 76mL in batches; Mixture with this reaction is cooled to 0 degree again, drips the 170mL acetic anhydride, stirs 2 hours at 110 degree; The TLC detection reaction finishes, and naturally cools to room temperature, in reaction mixture, adds the 500mL absolute ethyl alcohol; Filter, get 89g product (62%), MS (M+H)
+=239
Second step
With 10g (0.042mol) last one the step product, 7.2g (0.0504mol, 1.2eq) methyl iodide and 90mL toluene add in the tube sealing, are heated to 110 degree reactions and spend the night, and are cooled to room temperature, filter, and get the pure article of 15g (94%), MS (M+H)
+=253
The 3rd step
The second step product of 10g (26.3mmol) is dissolved in the methyl alcohol of 10mL, adds 0.2gPd/C, 15atm hydrogenation is spent the night under the room temperature, and TLC controls reaction end; Filter, revolve driedly, raffinate adds the sodium hydroxide solution of 20mL2M; At room temperature stir 30min, with ethyl acetate extraction (3*50mL), dried over mgso; Filter, revolve dried the pure article of 4.2g (95%), MS (M+H)
+=169
The 4th step
Under the nitrogen protection, (54mmol 3eq) with the anhydrous THF of 30mL, is cooled to 0 degree in three bottles of 200mL, to add the 2.05g Li-Al hydrogen; The product in the 3rd step of 3g (18mmol) is dissolved among the anhydrous THF of 50mL, is added drop-wise in the reaction flask, after dropwising, rise to room temperature naturally; Stir 30min, the 6h that refluxes then is cooled to 0 degree, drips 2.05g water, 4.1g15% aqueous sodium hydroxide solution and 2.5g water successively; Filter, filter cake is with ether washing (3*200mL), and filtrating merges organic phase with extracted with diethyl ether (3*200mL); Use dried over mgso, filtration is revolved dried, and underpressure distillation gets the pure article of 2.24g (89%), MS (M+H)
+=141.
IV. brief summary
The invention provides the synthetic and process method of one type of newtype drug midbody polynitrogen heterocycle.Utilize pyridine dicarboxylic acid cheap and that be easy to get to be raw material,, obtain nitrogenous bis-heterocyclic compounds through the reaction of 4 steps.Present method raw material is easy to get, and cost is low, and reaction is simple, is easy to control; Handle simply, yield is high, and is easy to amplify production; Include but not limited to aliphatics, aromatic series and heterocyclic polynitrogen heterocycle, the present invention provides the synthetic and process method of a practicable pharmaceutical intermediate for green chemical industry.
Claims (3)
1. one type has structural formula (III) 3, the synthetic and process method of the medicine intermediate polynitrogen heterocycle of 8-diazabicyclo [4.3.0] nonane class,
R wherein
3Be hydrogen, alkyl, phenyl, benzyl, cyclopropyl, heterocyclic radical; Said alkyl is selected from methyl, ethyl, sec.-propyl, isobutyl-; Said heterocyclic radical is selected from pyridyl, thienyl; It is characterized in that this method comprises the following step:
(1) reaction of pyridine dicarboxylic acid and benzylamine makes lactan; (2) lactan and R
3Br or R
3I react pyridinium salt; (3) the hydro-reduction pyridinium salt prepares the endocyclic compound of lactan; (4) with lithium aluminium hydride lactan is reduced into amine (III) 3,8-diazabicyclo [4.3.0] nonane class.
2. reach process method, wherein R according to synthesizing of claim 1
3Be hydrogen, methyl, ethyl, sec.-propyl, isobutyl-or cyclopropyl.
3. according to the synthetic and process method of claim 1 or 2, wherein the catalyzer that uses of the 3rd step hydro-reduction step is Pd/C, Pd (OH)
2/ C or Rh/C, reaction pressure 1-50kg/cm
2
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| CN104402891A (en) * | 2014-11-19 | 2015-03-11 | 苏州乔纳森新材料科技有限公司 | Synthetic method of drug intermediate 3-methyl-3,7-diazabicyclo(3.3.0)octane |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0603887A2 (en) * | 1992-12-25 | 1994-06-29 | Daiichi Pharmaceutical Co., Ltd. | Bicyclic amine derivatives |
| US5468742A (en) * | 1991-07-19 | 1995-11-21 | Bayer Aktiengesellschaft | 8-vinyl- and 9-ethinyl-quinolone-carboxylic acids |
| US6861425B2 (en) * | 2000-01-05 | 2005-03-01 | Pfizer, Inc. | Benzimidazole compounds as ORL1-receptor agonists |
-
2008
- 2008-07-01 CN CN2011100660224A patent/CN102101861B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5468742A (en) * | 1991-07-19 | 1995-11-21 | Bayer Aktiengesellschaft | 8-vinyl- and 9-ethinyl-quinolone-carboxylic acids |
| EP0603887A2 (en) * | 1992-12-25 | 1994-06-29 | Daiichi Pharmaceutical Co., Ltd. | Bicyclic amine derivatives |
| US6861425B2 (en) * | 2000-01-05 | 2005-03-01 | Pfizer, Inc. | Benzimidazole compounds as ORL1-receptor agonists |
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