CN109422675B - Synthesis method of novel monoamine oxidase inhibitor molabemide - Google Patents
Synthesis method of novel monoamine oxidase inhibitor molabemide Download PDFInfo
- Publication number
- CN109422675B CN109422675B CN201710725730.1A CN201710725730A CN109422675B CN 109422675 B CN109422675 B CN 109422675B CN 201710725730 A CN201710725730 A CN 201710725730A CN 109422675 B CN109422675 B CN 109422675B
- Authority
- CN
- China
- Prior art keywords
- chloro
- reaction
- solvent
- reflux
- molabemide
- 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.)
- Active
Links
Images
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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a synthesis method of a novel monoamine oxidase inhibitor molabemide, which comprises the steps of taking 5-chloro-2-pyridine carboxylic acid as a starting raw material, firstly carrying out acyl chlorination reaction to generate 5-chloro-2-pyridine formyl chloride, then carrying out amidation reaction to generate 5-chloro-N- (2-hydroxyethyl) -2-pyridine carboxamide, and finally condensing with morpholine to generate the molabemide. The compound molabemide adopts ethanolamine, 5-chloro-2-pyridine carboxylic acid and morpholine as main raw materials to prepare the novel monoamine oxidase inhibitor molabemide, and the raw materials are easy to obtain. The method for producing the moraxeine is simple to operate, high in product purity and yield and suitable for industrial production.
Description
Technical Field
The invention relates to the field of preparation of monoamine oxidase inhibitors, in particular to a synthesis method of a compound moraxeine.
Background
The name of the molabenamide is 5-chloro-N- [2- (4-morpholinyl) ethyl]-2-pyridinecarboxamide of formula C12H17ClN3O2The molecular weight is 268.72, the melting point is 160-164 ℃, and the crystal is white crystal. The NMR chart obtained by NMR measurement is shown in FIG. 1; the structural formula is as follows:
the only current method for synthesizing moraxeine is the application No. 201710191955.3. According to the synthesis method, ethanolamine and 5-chloro-2-pyridinecarboxylic acid are used as starting raw materials to respectively synthesize corresponding intermediates, namely 2-bromoethylamine hydrobromide and 5-chloro-2-pyridinecarboxylic acid chloride, then the two intermediates react to generate 5-chloro-N- (2-bromoethyl) -2-pyridinecarboxamide, and finally the obtained product is condensed with morpholine to generate the molabemide. The synthesis method is relatively complex to operate and relatively low in yield. The method is improved and innovated on the basis, 5-chloro-2-pyridinecarboxylic acid is used as a starting raw material, acyl chlorination reaction is firstly carried out to generate 5-chloro-2-pyridinecarboxylic acid chloride, amidation reaction is carried out to generate 5-chloro-N- (2-hydroxyethyl) -2-pyridinecarboxamide, and finally condensation is carried out with morpholine to generate the molabemide. The synthesis method has the advantages of few and simple operation steps and high yield, and is suitable for industrial production.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for synthesizing the compound molabemide with simple synthesis steps and high yield.
In order to achieve the purpose, the invention adopts the following technical scheme: a synthesis method of a novel monoamine oxidase inhibitor moraxeine comprises the following steps:
the preparation steps are as follows:
(1) synthesis of 5-chloro-2-pyridinecarbonyl chloride (b)
Firstly, adding 5-chloro-2-pyridinecarboxylic acid (a) into a solvent, adding N, N-Dimethylformamide (DMF) as a catalyst, uniformly stirring by magnetic force, and then dropwise adding thionyl chloride, wherein the molar ratio of the 5-chloro-2-pyridinecarboxylic acid to the thionyl chloride is 1:2, and the dropwise adding time is controlled to be 10-15 minutes; after the dropwise addition, heating for reflux reaction, and after the reflux is finished, removing the solvent and excessive thionyl chloride at normal pressure to obtain a white crystal 5-chloro-2-pyridine formyl chloride (b); the solvent is dichloromethane.
(2) Synthesis of 5-chloro-N- (2-hydroxyethyl) -2-pyridinecarboxamide (c)
Adding the 5-chloro-2-pyridine carbonyl chloride (b) obtained in the step (1) into a solvent, magnetically stirring for dissolving, then dropwise adding ethanolamine, wherein the molar ratio of the 5-chloro-2-pyridine carbonyl chloride to the ethanolamine is 1:2, the dropwise adding time is controlled to be 10-15 minutes, the reaction temperature is controlled to be 40-50 ℃, and after the dropwise adding is finished, keeping the temperature of 40-50 ℃ for continuous reaction for 2 hours; after the reaction is finished, removing the solvent under normal pressure, washing with water, filtering, drying, and recrystallizing with toluene to obtain a white crystal 5-chloro-N- (2-hydroxyethyl) -2-pyridinecarboxamide (c); the solvent is dichloromethane.
(3) Synthesis of moraxeine (d)
Adding 5-chloro-N- (2-hydroxyethyl) -2-pyridinecarboxamide (c) into toluene, heating to dissolve, then dropwise adding morpholine and a dehydrating agent, wherein the molar ratio of the 5-chloro-N- (2-hydroxyethyl) -2-pyridinecarboxamide (c) to the morpholine is 1:2, heating to reflux for reaction, cooling after the reaction is finished, carrying out suction filtration, and recrystallizing the toluene to obtain white solid molabemide (d).
The novel monoamine oxidase inhibitor molabemide prepared by the synthesis method can be used for preparing monoamine oxidase inhibitors and medicines containing the molabemide.
The compound molabemide adopts ethanolamine, 5-chloro-2-pyridine carboxylic acid and morpholine as main raw materials to prepare the novel monoamine oxidase inhibitor molabemide, and the raw materials are easy to obtain. The method for producing the molasseamine has the advantages of simple reaction line, no toxic intermediate in the synthetic route, simple operation, good product purity and higher yield, and is suitable for industrial production. The yield of the invention is 56%, while the yield of the invention is 46% in the patent with application number 201710191955.3, which is improved by 10% relatively. In addition, the invention only uses three steps to synthesize the moraxeine, and the invention uses four steps in the patent with the application number of 201710191955.3, so the reaction steps are simpler.
Drawings
FIG. 1 shows the hydrogen spectrum of a compound measured by Brucker ARX-300 NMR spectrometer.
Detailed Description
The method takes 5-chloro-2-pyridinecarboxylic acid as a starting material, generates 5-chloro-2-pyridinecarboxylic acid chloride through acyl chlorination reaction, generates 5-chloro-N- (2-hydroxyethyl) -2-pyridinecarboxamide through amidation reaction, and finally generates molabemide through condensation with morpholine. The synthetic route is as follows:
EXAMPLE 15 Synthesis of chloro-2-pyridinecarbonyl chloride (b)
Under the condition of 20-25 ℃, 5-chloro-2-pyridine carboxylic acid is firstly added into solvent dichloromethane, N-Dimethylformamide (DMF) is added as a catalyst, the mixture is stirred evenly by magnetic force, thionyl chloride is dripped, pyridine carboxylic acids Thionyl chloriden：n＝1:2The temperature of the reaction system is controlled to be not more than 30 ℃, and the time for dripping thionyl chloride is controlled to be 10-15 min. After the dropwise addition is finished, heating and carrying out reflux reaction for 6-8h, wherein the reflux temperature is 40-45 ℃, removing the solvent dichloromethane and excessive thionyl chloride under normal pressure after the reflux is finished, cooling and drying in vacuum to obtain white crystal 5-chloro-2-pyridine carbonyl chloride. The yield is 98 percent, the purity is 99.4 percent, and the melting point is 218 ℃ and 220 ℃.
EXAMPLE 25 Synthesis of chloro-N- (2-hydroxyethyl) -2-pyridinecarboxamide (c)
Firstly adding 5-chloro-2-pyridine formyl chloride (b) into solvent dichloromethane, magnetically stirring for dissolving, then dropwise adding ethanolamine, pyridine carbonyl chloride Ethanolaminen：n＝1:2The dripping time is controlled to be 10-15 minutes, the reaction temperature is controlled to be 40-50 ℃, and the reaction is continued for 2-4 hours after the dripping is finished and the temperature is kept at 40-50 ℃. After the reaction is finished, the solvent is removed under normal pressure, and the white crystal 5-chloro-N- (2-hydroxyethyl) -2-pyridinecarboxamide (c) is obtained by washing, filtering, drying and toluene recrystallization. The yield is 93%, the purity is 99.3%, and the melting point is 117-.
Example 3 Synthesis of Morabemide (d)
Adding 5-chloro-N- (2-hydroxyethyl) -2-pyridinecarboxamide (c) into solvent toluene, heating to dissolve, dripping morpholine and 98% concentrated sulfuric acid after complete dissolution, pyridine carboxamide Morpholinen：n＝1:2Heating reflux reaction for 12-16h at 120-125 ℃. And after the reaction is finished, cooling, performing suction filtration, and recrystallizing toluene to obtain white solid molabemide. The yield is 56%, the purity is 99.5%, and the melting point is 162-.
The relative molecular mass is 268.72 and the melting point is 162-164 ℃ by mass spectrometry, and the crystal is white crystal; FIG. 1 shows the NMR chart obtained by NMR measurement.
Comparative analysis of example 4 with reference (application No. 201710191955.3)
In a comparison document (application number 201710191955.3) of the background art, moraxeine is synthesized in four steps, wherein a large amount of 40% hydrobromic acid is used in the synthesis of 2-bromoethylamine hydrobromide, the hydrobromic acid is relatively corrosive to synthesis equipment, and after salification, the hydrobromic acid needs to be eluted in the next step, so that the operation is relatively complex and the time consumption is relatively long. In addition, the last step in the comparison document is condensed with morpholine to generate the molabemide, the step belongs to substitution reaction, and because the morpholine belongs to imine for substitution, the yield of the step is lower than 46%. The invention synthesizes the molasseamine only by three steps, and has better advantages in the synthesis step. According to the invention, 5-chloro-2-pyridinecarboxylic acid is subjected to acyl chlorination reaction, then directly subjected to amidation reaction with ethanolamine, and finally subjected to condensation reaction to generate the molassesamine, so that the operation is simple, corrosive raw materials are not used, and the like. The final step of the invention also takes the form of condensation, but the condensation in the dehydrated form is easier than that in the substituted form, so that the yield in this step is 56%, which is 46% higher than that in the reference. In addition, the invention also reduces the raw material proportion, the dosage of the thionyl chloride is 2 parts, and the dosage of the thionyl chloride is 4 parts in a comparison document; the consumption of morpholine is 2 parts, the consumption of morpholine is 3 parts in a comparison document, and the like, thereby reducing the synthesis cost.
Claims (1)
1. A synthesis method of a novel monoamine oxidase inhibitor moraxeine comprises the following steps:
the preparation steps are as follows:
(1) synthesis of 5-chloro-2-pyridinecarbonyl chloride (b)
Firstly, adding 5-chloro-2-pyridinecarboxylic acid (a) into a solvent, adding N, N-Dimethylformamide (DMF) as a catalyst, uniformly stirring by magnetic force, and then dropwise adding thionyl chloride, wherein the molar ratio of the 5-chloro-2-pyridinecarboxylic acid to the thionyl chloride is 1:2, and the dropwise adding time is controlled within 10-15 minutes; after the dropwise addition, heating for reflux reaction, and after the reflux is finished, removing the solvent and excessive thionyl chloride at normal pressure to obtain a white crystal 5-chloro-2-pyridine formyl chloride (b); the solvent is dichloromethane;
(2) synthesis of 5-chloro-N- (2-hydroxyethyl) -2-pyridinecarboxamide (c)
Adding the 5-chloro-2-pyridine carbonyl chloride (b) obtained in the step (1) into a solvent, magnetically stirring for dissolving, then dropwise adding ethanolamine, wherein the molar ratio of the 5-chloro-2-pyridine carbonyl chloride to the ethanolamine is 1:2, the dropwise adding time is controlled to be 10-15 minutes, the reaction temperature is controlled to be 40-50 ℃, and the reaction is continued after the dropwise adding is finished; after the reaction is finished, removing the solvent under normal pressure, washing with water, filtering, drying, and recrystallizing with toluene to obtain a white crystal 5-chloro-N- (2-hydroxyethyl) -2-pyridinecarboxamide (c); the solvent is dichloromethane;
(3) synthesis of moraxeine (d)
Adding 5-chloro-N- (2-hydroxyethyl) -2-pyridinecarboxamide (c) into a solvent, heating to dissolve, then dropwise adding morpholine and a dehydrating agent, wherein the molar ratio of the 5-chloro-N- (2-hydroxyethyl) -2-pyridinecarboxamide (c) to the morpholine is 1:2, heating to reflux for reaction, cooling after the reaction is finished, carrying out suction filtration, and recrystallizing toluene to obtain white solid molabemide (d); the solvent is toluene;
in the step (1), the reflux temperature of the heating reflux reaction is 40-45 ℃, the reflux time is 6-8h, and the catalyst is DMF;
after the dropwise adding in the step (2) is finished, the reaction temperature for continuing the reaction is 40-45 ℃, the reaction time is 2-4h, and the solvent is dichloromethane;
the reaction time of the heating reflux reaction in the step (3) is 12-16h, the reflux temperature is 120-125 ℃, the solvent is toluene, and the dehydrating agent is 98% concentrated sulfuric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710725730.1A CN109422675B (en) | 2017-08-22 | 2017-08-22 | Synthesis method of novel monoamine oxidase inhibitor molabemide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710725730.1A CN109422675B (en) | 2017-08-22 | 2017-08-22 | Synthesis method of novel monoamine oxidase inhibitor molabemide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109422675A CN109422675A (en) | 2019-03-05 |
| CN109422675B true CN109422675B (en) | 2022-03-08 |
Family
ID=65497920
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710725730.1A Active CN109422675B (en) | 2017-08-22 | 2017-08-22 | Synthesis method of novel monoamine oxidase inhibitor molabemide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109422675B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113558010A (en) * | 2021-07-19 | 2021-10-29 | 重庆师范大学 | Method for establishing zebra fish depression model and determining anti-depression activity of moraxella berbamine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1160047A (en) * | 1996-03-18 | 1997-09-24 | 国家医药管理局上海医药工业研究院 | Method for preparing moclobemide |
| CN102105475A (en) * | 2008-07-28 | 2011-06-22 | 卫材R&D管理有限公司 | Spiroaminodihydrothiazine derivatives |
| CN108658852A (en) * | 2017-03-28 | 2018-10-16 | 重庆师范大学 | Noval chemical compound draws shellfish amine, preparation method and the usage |
-
2017
- 2017-08-22 CN CN201710725730.1A patent/CN109422675B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1160047A (en) * | 1996-03-18 | 1997-09-24 | 国家医药管理局上海医药工业研究院 | Method for preparing moclobemide |
| CN102105475A (en) * | 2008-07-28 | 2011-06-22 | 卫材R&D管理有限公司 | Spiroaminodihydrothiazine derivatives |
| CN108658852A (en) * | 2017-03-28 | 2018-10-16 | 重庆师范大学 | Noval chemical compound draws shellfish amine, preparation method and the usage |
Non-Patent Citations (3)
| Title |
|---|
| Oxazolines 3.1 Regioselective synthesis of 2-(Monosubstituted phenyl) and/or unsymmetrically 2-(disubstitued phenyl) 2-oxazolines by cross-coupling Grignard reagents to (Haloaryl)-2-oxazolines;Lendon N. Pridgen;《J. Org. Chem.》;19821231;第47卷(第22期);第4323页左栏第1-9段 * |
| Synthesis of 11,12-Bis(ary-amido/imido-alkyl)-12-H-benzo[b]phenothiazines as potential anthelmintics;V K Pandey et al.;《Indian Journal of Chemistry: Section B》;19871231;第26B卷(第12期);第1208页Table1和第1209页Scheme1; 第1210页左栏第3-4段 * |
| 第1210页左栏第3-4段. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109422675A (en) | 2019-03-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101472686B1 (en) | Method for preparation of benzimidazole derivatives | |
| JP2020097607A (en) | Novel manufacturing method of chromanone derivative | |
| JP2013040196A (en) | Process for preparing piperazine derivative | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN109422675B (en) | Synthesis method of novel monoamine oxidase inhibitor molabemide | |
| WO2016045416A1 (en) | Intermediate for use in synthesizing paroxetine, preparation method for the intermediate, and uses thereof | |
| CN108912044A (en) | A kind of method of copper catalysis alkenyl azide synthesis polysubstituted pyridine | |
| CN106699595A (en) | Preparation method for lacosamide | |
| CN108164423B (en) | Preparation method of naftifine hydrochloride | |
| JP6781030B2 (en) | L-carnosine derivative or salt thereof, and method for producing L-carnosine or salt thereof | |
| CN107868033B (en) | Preparation method of phenylalanine compound | |
| CN111004141B (en) | New method for synthesizing nintedanib intermediate 2-chloro-N-methyl-N- (4-nitrophenyl) acetamide | |
| CN108586379B (en) | Preparation method of 3-aminofurazan-4-formamide | |
| CN109369618B (en) | Method for preparing 2-chloro-5- ((2- (nitromethylene) imidazoline-1-yl) methyl) pyridine in one pot | |
| CN118239886A (en) | Morabamine compound and preparation method and application thereof | |
| CN108794396B (en) | Oxidation method of 4-oxo-2, 3-dihydroquinoline compound | |
| TW202210486A (en) | Method for preparing glp-1 receptor agonist | |
| CN112778220B (en) | Preparation method of benzodiazepine diketone compound D and intermediate thereof | |
| CN107573263B (en) | Synthetic method of omega-substituted biuret compound | |
| KR20090064456A (en) | Process for the preparation of trifluoroethoxytoluenes | |
| CN105218490B (en) | Preparation method of (R)-tetrahydrofuran-3-amine | |
| JP5582682B2 (en) | Method for producing substituted 4-alkoxycarbonyl-3-aminothiophenes | |
| KR20130134407A (en) | Process for preparing gefitinib and an intermediate used for preparing thereof | |
| CN107151197B (en) | Preparation method of 9-bromophenanthrene | |
| CN100383144C (en) | Intermediate of olanzapine, preparation and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |