CN104356051A - Analgesic intermediate and synthesis method thereof - Google Patents
Analgesic intermediate and synthesis method thereof Download PDFInfo
- Publication number
- CN104356051A CN104356051A CN201410681448.4A CN201410681448A CN104356051A CN 104356051 A CN104356051 A CN 104356051A CN 201410681448 A CN201410681448 A CN 201410681448A CN 104356051 A CN104356051 A CN 104356051A
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- CN
- China
- Prior art keywords
- analgesic
- piperidine
- intermediate compound
- propyl
- carboxylic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
Abstract
The invention discloses an analgesic intermediate, which has a structure (as shown in Specification), as well as a synthesis method of the analgesic intermediate. A synthesis route (as shown in Specification) is as follows: adding propyl alcohol to a reaction flask, preserving temperature at -10 DEG C, dropping thionyl chloride, cooling to -5 DEG C after dropping, adding 4-piperidine carboxylic acid in batches, preserving the heat at 0 DEG C and reacting for 2h after adding, recovering to room temperature and reacting until white solid is completely dissolved. The piperidine ring-containing analgesic intermediate 4-propyl carboxylate piperidine synthesized by the method disclosed by the invention is moderate in polarity, and shows good solubility in most organic solvents; the synthesized analgesic, which takes the 4-propyl carboxylate piperidine as intermediate, greatly reduces addiction; and the compound can prepare a series of medicines having analgesic activity, and has wide scientific research medicinal value.
Description
Technical field
The present invention relates to a kind of analgesic intermediate compound and synthetic method thereof.
Background technology
Anodyne refers to the class medicine alleviating pain.Anodyne has analgesia, calmness, antibechic and suppresses breathing, miosis, the effect such as emetic.Its analgesic activity has high efficiency, selectivity and three-dimensional arrangement specificity, meets the feature with receptor binding drug.Anodyne, in maincenter and peripheral nervous system but is seldom affected other sensoriums the selective restraining effect of pain sensation maincenter by different mechanisms.Anodyne is mostly opioid drug (as morphine) and Synthetic artifact (as Pethidine, pentazocine etc.) thereof, the sharp pains (being distinguish part with antipyretic and analgesic) such as fracture, burn can be alleviated, long-term continuous application, has additive more.
Summary of the invention
The invention provides a kind of analgesic intermediate compound and synthetic method thereof, to overcome the above-mentioned defect existed in prior art.
In order to achieve the above object, technical scheme of the present invention is: a kind of analgesic intermediate compound, has following structure
A synthetic method for above-mentioned analgesic intermediate compound, synthetic route is:
Step comprises: add propyl alcohol in reaction flask, keeps temperature-10 DEG C, drips thionyl chloride, dropwises, be cooled to-5 DEG C, add 4-piperidine carboxylic acid in batches, after finishing, keeps 0 DEG C of reaction 2 hours, returns to room temperature, react to white solid and all dissolve.
As preferably, the amount of substance of thionyl chloride is 2 times of the amount of substance of 4-piperidine carboxylic acid.
As preferably, after returning to room temperature, react 24 hours.
The present invention synthesizes a kind of analgesic drug intermediate 4-propyl carboxylate piperidines containing piperidine ring, this compound polarity is moderate, good solubleness is had in majority of organic solvent, with 4-propyl carboxylate piperidines for intermediate, the analgesic drug of synthesis is additive to be reduced greatly, this compound can prepare a series of medicine with analgesic activities, has scientific research pharmaceutical use widely.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.
25mL propyl alcohol, keeps temperature-10 DEG C, slowly drips 6mL thionyl chloride, control rate of addition, make mixture remain on less than 0 DEG C, within 1.5 hours, dropwise, be cooled to-5 DEG C, then add 3.25 grams of 4-piperidine carboxylic acids, after finishing in batches, keep 0 DEG C to react 2 hours, return to room temperature, stir 24 hours, all dissolve to white solid, after reaction terminates, underpressure distillation thionyl chloride too and propyl alcohol, obtain white solid, washed with diethylether, after drying, obtain 4 grams of 4-propyl carboxylate piperidine product.
In the esterification reaction process of 4-piperidine carboxylic acid, by being first acyl chlorides by Carboxylic Acid, substantially increase the activity of carbonylic carbon atom in reaction like this, corresponding ester is obtained by reacting again to propyl alcohol, and the reactant propyl alcohol adopted is as solvent, reaction is carried out completely, and yield is higher.
Those skilled in the art can carry out various change and modification to invention and not depart from the spirit and scope of the present invention.Like this, if these amendments of the present invention and modification belong within the scope of the claims in the present invention and equivalent technologies thereof, then the present invention is also intended to comprise these change and modification.
Claims (4)
1. an analgesic intermediate compound, is characterized in that, has following structure
2. a synthetic method for analgesic intermediate compound according to claim 1, is characterized in that, synthetic route is:
Step comprises: add propyl alcohol in reaction flask, keeps temperature-10 DEG C, drips thionyl chloride, dropwises, be cooled to-5 DEG C, add 4-piperidine carboxylic acid in batches, after finishing, keep 0 DEG C to react 2 hours, return to room temperature, react to white solid and all dissolve, 4-propyl carboxylate piperidines.
3. the synthetic method of analgesic intermediate compound according to claim 2, is characterized in that, the amount of substance of thionyl chloride is 2 times of the amount of substance of 4-piperidine carboxylic acid.
4. the synthetic method of analgesic intermediate compound according to claim 2, is characterized in that, reacts 24 hours after returning to room temperature.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410681448.4A CN104356051A (en) | 2014-11-24 | 2014-11-24 | Analgesic intermediate and synthesis method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410681448.4A CN104356051A (en) | 2014-11-24 | 2014-11-24 | Analgesic intermediate and synthesis method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104356051A true CN104356051A (en) | 2015-02-18 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410681448.4A Pending CN104356051A (en) | 2014-11-24 | 2014-11-24 | Analgesic intermediate and synthesis method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104356051A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999025685A1 (en) * | 1997-11-18 | 1999-05-27 | Merck & Co., Inc. | 4-substituted-4-piperidine carboxamide derivatives |
| WO2003048126A1 (en) * | 2001-11-15 | 2003-06-12 | Glaxo Group Limited | Process for the preparation of (2s)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy) phenyl]2-{((2s)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino[propanoic acid and intermediates therefore |
| CN101209990A (en) * | 2006-12-26 | 2008-07-02 | 江苏天汁化学有限公司 | Resolution method for 3-piperidine formic acid ester |
| CN101525313A (en) * | 2009-04-29 | 2009-09-09 | 中国人民解放军防化指挥工程学院 | 4-substituted and N-substituted ethyl 4-piperidinecarboxylate compounds and preparation methods thereof |
| CN103641772A (en) * | 2013-12-19 | 2014-03-19 | 北京成宇化工有限公司 | Preparation method of (2R, 4R)-4-pipecolines-2-ethyl formate compound |
-
2014
- 2014-11-24 CN CN201410681448.4A patent/CN104356051A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999025685A1 (en) * | 1997-11-18 | 1999-05-27 | Merck & Co., Inc. | 4-substituted-4-piperidine carboxamide derivatives |
| WO2003048126A1 (en) * | 2001-11-15 | 2003-06-12 | Glaxo Group Limited | Process for the preparation of (2s)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy) phenyl]2-{((2s)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino[propanoic acid and intermediates therefore |
| CN101209990A (en) * | 2006-12-26 | 2008-07-02 | 江苏天汁化学有限公司 | Resolution method for 3-piperidine formic acid ester |
| CN101525313A (en) * | 2009-04-29 | 2009-09-09 | 中国人民解放军防化指挥工程学院 | 4-substituted and N-substituted ethyl 4-piperidinecarboxylate compounds and preparation methods thereof |
| CN103641772A (en) * | 2013-12-19 | 2014-03-19 | 北京成宇化工有限公司 | Preparation method of (2R, 4R)-4-pipecolines-2-ethyl formate compound |
Non-Patent Citations (1)
| Title |
|---|
| RAVISH C. TRIPATHI，等: "SYNTHESIS AND SAR STUDIES OF 1-SUBSTITUTED-n-(4-ALKOXYCARBONYLPIPERIDIN-1-YL)ALKANES AS POTENT ANTIARRHYTHMIC AGENTS #", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150218 |