CN104163788A - Preparation method of pyridine derivative - Google Patents
Preparation method of pyridine derivative Download PDFInfo
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- CN104163788A CN104163788A CN201410319642.8A CN201410319642A CN104163788A CN 104163788 A CN104163788 A CN 104163788A CN 201410319642 A CN201410319642 A CN 201410319642A CN 104163788 A CN104163788 A CN 104163788A
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- reaction
- prepared compound
- nucleophilic substitution
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- temperature
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- BHRQPRCVTKWGMM-UHFFFAOYSA-N CC(C)(C)OC(N1CCN(CCN(C=CC=C2)C2=O)CC1)=O Chemical compound CC(C)(C)OC(N1CCN(CCN(C=CC=C2)C2=O)CC1)=O BHRQPRCVTKWGMM-UHFFFAOYSA-N 0.000 description 1
- PJWNJWGPRUXBMC-UHFFFAOYSA-N O=C1N(CCCl)C=CC=C1 Chemical compound O=C1N(CCCl)C=CC=C1 PJWNJWGPRUXBMC-UHFFFAOYSA-N 0.000 description 1
- IFGLYFGMVPARFN-UHFFFAOYSA-N O=C1N(CCN2CCNCC2)C=CC=C1 Chemical compound O=C1N(CCN2CCNCC2)C=CC=C1 IFGLYFGMVPARFN-UHFFFAOYSA-N 0.000 description 1
- OSAKOAYGMSTAKA-UHFFFAOYSA-N OCCN(C=CC=C1)C1=O Chemical compound OCCN(C=CC=C1)C1=O OSAKOAYGMSTAKA-UHFFFAOYSA-N 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N Oc1ncccc1 Chemical compound Oc1ncccc1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Abstract
The invention discloses a preparation method of a pyridine derivative, and especially relates to a preparation method of 1-(2-(piperazine-1-group)ethyl)pyridine-2(1H)-ketone, the method takes 2-pyridone as an initial raw material, and 2-pyridone is subjected to nucleophilic substitution, chlorination, nucleophilic substitution and Boc removal to obtain the target product, and the compound is an important medicine intermediate.
Description
Technical field
The present invention relates to a kind of novel preparation method of medicine intermediate, a kind of preparation method of special 1-(2-(piperazine-1-yl) ethyl) pyridine-2 (1H)-one.
Technical background
Compound 1-(2-(piperazine-1-yl) ethyl) pyridine-2 (1H)-one, English 1-(2-(piperazin-1-yl) ethyl) pyridine-2 (1H)-one by name, structural formula is:
Antimicrobial agents is that current clinical application is wide, a class medicine of large usage quantity, aspect control and treatment disease, is playing an important role.The antimicrobial agents kind of current clinical use is numerous, but is widely used along with a large amount of of antimicrobial agents, particularly unreasonable application clinically, and even abuse, finally causes multidrug resistant.Therefore, how to overcome multidrug resistant and become the important topic of antimicrobial agents research both at home and abroad at present.The method that solves resistance is numerous, and wherein the research and development of novel texture antimicrobial agents are to solve one of important channel of resistance, have become the very active field of current pharmaceutical chemistry.
Pyridine derivate group is a class basic group conventional in pharmaceutical chemistry research, and its toxicity is little, easily forms a plurality of hydrogen bonds or ionic linkage, often the lipid of regulating drug and acid base equilibrium constant effectively.Be introduced into molecule, can effectively increase the alkalescence of molecule and water-soluble, thereby strengthen the activity of molecule.Therefore, to a certain extent, pyridine derivate group is a synergy group, in the design and development of many medicines of being everlasting, introduces.Research shows, containing the compound of pyridine, often demonstrates biological activity widely, and as antimicrobial, hypertension, anticancer, anti-inflammatory and pain relieving etc., especially as antimicrobial agents, the active and development of its research rapidly, demonstrates broad development potentiality.
The 1-the present invention relates to (2-(piperazine-1-yl) ethyl) pyridine-2 (1H)-one has vital role for new drug development.
Summary of the invention
The invention discloses the method for a kind of 1-of preparation (2-(piperazine-1-yl) ethyl) pyridine-2 (1H)-one, take 2 hydroxy pyrimidine as starting raw material, through nucleophilic substitution, chlorination, nucleophilic substitution, de-Boc, obtain target product 5.Synthetic route as shown in Figure 1.Synthesis step is as follows:
(1) take 2 hydroxy pyrimidine as starting raw material, nucleo philic substitution reaction obtains 2;
(2) 2, carry out chlorination reaction, obtain 3;
(3) 3, carry out nucleophilic substitution reaction and obtain 4;
(4) 4, take off Boc and obtain target product 5,
One preferred embodiment in, described nucleophilic substitution reaction is prepared compound 2 alkali used and is selected from salt of wormwood; Described chlorination reaction is prepared compound 3 chlorizating agent used and is selected from sulfur oxychloride; Described nucleophilic substitution reaction is prepared compound 4 alkali used used and is selected from salt of wormwood; Described de-Boc reaction is prepared compound 5 deprotection agent used and is selected from hydrochloric acid.
One preferred embodiment in, described nucleophilic substitution reaction is prepared compound 2 solvent used and is selected from DMF; Described chlorination reaction is prepared compound 3 solvent used and is selected from sulfur oxychloride; Described nucleophilic substitution reaction is prepared compound 4 solvent used and is selected from tetrahydrofuran (THF); Described de-Boc reaction is prepared compound 5 solvent used and is selected from methylene dichloride.
One preferred embodiment in, it is the reflux temperature of solvent that described nucleophilic substitution reaction is prepared compound 2 temperature of reaction used; It is the reflux temperature of solvent that described chlorination reaction is prepared compound 3 temperature used; It is the reflux temperature of solvent that described nucleophilic substitution reaction is prepared compound 4 temperature used; Described de-Boc reaction prepare compound 5 used be room temperature.
The preparation method who the present invention relates to a kind of pyridine derivate 1-(2-(piperazine-1-yl) ethyl) pyridine-2 (1H)-one, does not have other Patents bibliographical informations at present.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of pyridine derivate 1-(2-(piperazine-1-yl) ethyl) pyridine-2 (1H)-one.
The present invention is further described by the following embodiment, and these descriptions are not that content of the present invention is further limited.One skilled in the art will understand that the replacement that is equal to that technical characterictic of the present invention is done, or improve accordingly, within still belonging to protection scope of the present invention.
Specific embodiment mode
Embodiment 1
(1) 1-(2-hydroxyethyl) pyridine-2 (1H)-one is synthetic
20g2-pyridone is joined to 500ml N, in dinethylformamide, add 9g Anhydrous potassium carbonate, add again 40g2-bromoethanol, reflux stirs 8 hours, is cooled to room temperature, adds water to extract, separatory, dry, concentrated, the separation of residuum upper prop obtains 23g1-(2-hydroxyethyl) pyridine-2 (1H)-one.
(2) 1-(2-chloroethyl) pyridine-2 (1H)-one is synthetic
22g1-(2-hydroxyethyl) pyridine-2 (1H)-one is joined in 140ml sulfur oxychloride, reflux 6 hours, be cooled to room temperature, unnecessary sulfur oxychloride is removed in decompression, add water and ethyl acetate, extraction separatory, collects organic phase again, separatory, dry, concentrated, separated 18g1-(2-chloroethyl) pyridine-2 (1H)-one that obtains of silicagel column on residuum.
(3) tertiary butyl 4-(2-(2-oxo pyridine-1 (2H)-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester is synthetic
15g1-(2-chloroethyl) pyridine-2 (1H)-one is joined in 400ml tetrahydrofuran (THF), add 6g Anhydrous potassium carbonate, add again 21g1-Boc-piperazine, reflux 13 hours, is cooled to room temperature, adds water and ethyl acetate, extraction separatory, collect organic phase, separatory, dry, concentrated, separated 26g tertiary butyl 4-(2-(2-oxo pyridine-1 (2H)-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester that obtains of silicagel column on residuum.
(4) 1-(2-(piperazine-1-yl) ethyl) pyridine-2 (1H)-one is synthetic
25g tertiary butyl 4-(2-(2-oxo pyridine-1 (2H)-yl) ethyl) piperazine-1-carboxylic acid tert-butyl ester is joined in 400ml methylene dichloride, pass into hydrogenchloride until saturated, stir 24 hours, filter, filter cake joins in saturated sodium bicarbonate aqueous solution, be extracted with ethyl acetate separatory, collect organic phase, separatory, dry, concentrated 1-(2-(piperazine-1-yl) ethyl) pyridine-2 (1H)-one that obtains.
Claims (6)
1. prepare a method for 1-(2-(piperazine-1-yl) ethyl) pyridine-2 (1H)-one, take 2 hydroxy pyrimidine as starting raw material, through nucleophilic substitution, chlorination, nucleophilic substitution, de-Boc, obtain target product 5, synthetic route is as follows.
2. according to the method for claim 1,4 steps described in it is characterized by are reacted and are,
(1) take 2 hydroxy pyrimidine as starting raw material, nucleo philic substitution reaction obtains 2;
(2) 2, carry out chlorination reaction, obtain 3;
(3) 3, carry out nucleophilic substitution reaction and obtain 4;
(4) 4, take off Boc and obtain target product 5,
3. according to the method for claim 1-2, it is characterized in that, described nucleophilic substitution reaction is prepared compound 2 alkali used and is selected from one or more the mixture in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus; Described chlorination reaction is prepared compound 3 chlorizating agent used and is selected from one or more the mixture in sulfur oxychloride, chlorine, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride; Described nucleophilic substitution reaction is prepared compound 4 alkali used used and is selected from one or more the mixture in sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, salt of wormwood, sodium hydride, triethylamine, sodium bicarbonate, pyridine, triisopropylamine, saleratus; Described de-Boc reaction is prepared compound 5 deprotection agent used and is selected from one or more the mixture in hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid.
4. according to the method for claim 1-2, it is characterized in that, described nucleophilic substitution reaction is prepared compound 2 solvent used and is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described chlorination reaction is prepared compound 3 solvent used and is selected from methylene dichloride, trichloromethane, ethyl acetate, tetrahydrofuran (THF), toluene, tetrahydrofuran (THF), toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide, sulfur oxychloride, phosphorus oxychloride; Described nucleophilic substitution reaction is prepared compound 4 solvent used and is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide; Described de-Boc reaction is prepared compound 5 solvent used and is selected from methyl alcohol, ethanol, n-propyl alcohol, Virahol, tetrahydrofuran (THF), methylene dichloride, trichloromethane, ethyl acetate, toluene, o-Xylol, p-Xylol, m-xylene, N, the mixture of one or more in dinethylformamide, N,N-dimethylacetamide.
5. according to the method for claim 1-2, it is characterized in that, it is the reflux temperature of 0 ℃～solvent that described nucleophilic substitution reaction is prepared compound 2 temperature of reaction used; It is the reflux temperature of 0 ℃～solvent that described chlorination reaction is prepared compound 3 temperature used; It is the reflux temperature of 0 ℃～solvent that described nucleophilic substitution reaction is prepared compound 4 temperature used; Described de-Boc reaction prepare compound 5 used be 0 ℃～room temperature.
6. according to the method for claim 1-2, it is characterized in that, it is the reflux temperature of solvent that described nucleophilic substitution reaction is prepared compound 2 temperature of reaction used; It is the reflux temperature of solvent that described chlorination reaction is prepared compound 3 temperature used; It is the reflux temperature of solvent that described nucleophilic substitution reaction is prepared compound 4 temperature used; Described de-Boc reaction prepare compound 5 used be room temperature.
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| CN201410319642.8A CN104163788A (en) | 2014-07-07 | 2014-07-07 | Preparation method of pyridine derivative |
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| CN201410319642.8A CN104163788A (en) | 2014-07-07 | 2014-07-07 | Preparation method of pyridine derivative |
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003084959A1 (en) * | 2002-04-03 | 2003-10-16 | Bristol-Myers Squibb Company | Thiopene-based tricyclic compounds and pharmaceutical compositions comprising same |
| US20040024206A1 (en) * | 2001-11-30 | 2004-02-05 | Lijun Sun | Pyrimidine compounds |
| CN1527820A (en) * | 2001-05-18 | 2004-09-08 | 4-(phenyl-piperazinyl-methyl)benzamide derivatives and their use for the treatment of pain, anxiety or gastrointestional disorders | |
| WO2011057229A2 (en) * | 2009-11-09 | 2011-05-12 | University Of Miami | Fluorescent analogs of neurotransmitters, compositions containing the same and methods of using the same |
| CN102159589A (en) * | 2008-09-17 | 2011-08-17 | 霍夫曼-拉罗奇有限公司 | Neuropeptide-2 receptor (y-2r) agonists and uses thereof |
| CN102548992A (en) * | 2009-07-30 | 2012-07-04 | Irm责任有限公司 | 2, 7 -naphthyridin- 1 -one derivatives as syk kinase inhibitors |
| CN102731437A (en) * | 2012-06-15 | 2012-10-17 | 盛世泰科生物医药技术(苏州)有限公司 | Preparation method of 4-piperazine-3-trifluoromethylaniline hydrochloride |
| CN102993122A (en) * | 2012-12-24 | 2013-03-27 | 武汉武药制药有限公司 | Novel synthesis path of trimetazidine hydrochloride |
-
2014
- 2014-07-07 CN CN201410319642.8A patent/CN104163788A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1527820A (en) * | 2001-05-18 | 2004-09-08 | 4-(phenyl-piperazinyl-methyl)benzamide derivatives and their use for the treatment of pain, anxiety or gastrointestional disorders | |
| US20040024206A1 (en) * | 2001-11-30 | 2004-02-05 | Lijun Sun | Pyrimidine compounds |
| WO2003084959A1 (en) * | 2002-04-03 | 2003-10-16 | Bristol-Myers Squibb Company | Thiopene-based tricyclic compounds and pharmaceutical compositions comprising same |
| CN102159589A (en) * | 2008-09-17 | 2011-08-17 | 霍夫曼-拉罗奇有限公司 | Neuropeptide-2 receptor (y-2r) agonists and uses thereof |
| CN102548992A (en) * | 2009-07-30 | 2012-07-04 | Irm责任有限公司 | 2, 7 -naphthyridin- 1 -one derivatives as syk kinase inhibitors |
| WO2011057229A2 (en) * | 2009-11-09 | 2011-05-12 | University Of Miami | Fluorescent analogs of neurotransmitters, compositions containing the same and methods of using the same |
| CN102731437A (en) * | 2012-06-15 | 2012-10-17 | 盛世泰科生物医药技术(苏州)有限公司 | Preparation method of 4-piperazine-3-trifluoromethylaniline hydrochloride |
| CN102993122A (en) * | 2012-12-24 | 2013-03-27 | 武汉武药制药有限公司 | Novel synthesis path of trimetazidine hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| SACHA A.: "Search for pharmacologically active piperazie compounds. VI. New method of obtaining 4-substituted 1-(beta-(N-pyridono-2)ethyl)-piperazine", 《ACTA POLONIAE PHARMACEUTICA》, vol. 30, no. 3, 31 December 1973 (1973-12-31), pages 265 - 270 * |
| SACHA A.: "Search for pharmacologically active piperazine. II. 1-(N-ethylenepyridone-2)-4- arylpiperazines and 1-(N-ethylenepyridono-2)-4-aralkylpiperazines", 《ACTA POLONIAE PHARMACEUTICA》, vol. 22, no. 5, 31 December 1965 (1965-12-31), pages 411 - 417 * |
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Application publication date: 20141126 |