CN103396332A - 3-[(N-methyl-N-pentyl)amino]propionic acid hydrochloride preparation method - Google Patents
3-[(N-methyl-N-pentyl)amino]propionic acid hydrochloride preparation method Download PDFInfo
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Abstract
The present invention relates to a 3-[(N-methyl-N-pentyl)amino]propionic acid hydrochloride preparation method, wherein n-amylamine and acrylate are subjected to a Michael addition reaction to obtain 3-(N-pentylamino)propionate, and the 3-(N-pentylamino)propionate reacts with formic acid and formaldehyde to obtain the 3-[(N-methyl-N-pentyl)amino]propionic acid hydrochloride. The method has characteristics of easily available and cheap starting materials, high yield, simple operation and high product purity, and is suitable for large-scale industrial production.
Description
Technical field:
The present invention relates to the preparation method of the key intermediate 3 of medicine ibronate sodium-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorate.
Background technology:
Ibronate sodium (Ibandronate Monosodium) belongs to third generation bisphosphonate class of drugs, has efficient, low toxicity and the advantage such as easy to use, and oral and two kinds of formulations of vein are arranged simultaneously, is rare biphosphonates.Ibronate sodium is by Hoffmann-La Roche company exploitation, the research of Abroad in Recent Years has obtained breakthrough, except the treatment malignant metastatic tumor of bone, can also prevent bone transfer and Bone of Breast Cancer to shift the generation of rear bone event, and can prevent and treat osteoporosis.It is the widest biphosphonates of present indication.
3-(N-methyl-N-amyl group) alanine hydrochlorides are key intermediates of synthetic ibronate sodium (Ibandronate Monosodium).
Patent US4927814 discloses ibronate sodium (Ibandronate Monosodium) class medicine, and wherein the synthetic method of key intermediate 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorate is as follows:
The method synthetic route is long, and reaction is complicated, uses the precious metal palladium catalytic hydrogenation twice, and cost is high, and hydrogenation danger is high, and is high to equipment requirements.
Patent WO2006045578 discloses the synthetic method of 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates, and US4927814 is had to further improvement, has got rid of this step of palladium charcoal catalysis, and synthetic method is as follows:
It becomes Schiff's base first take n-amylamine as starting raw material with the phenyl aldehyde reaction, and then with a methyl-sulfate upper methyl in amino under 90-100 ℃ formerly, obtain N-methyl n-amylamine, and then carry out the Michael addition reaction with methyl acrylate.Reactions steps is long, the reaction conditions complexity, and side reaction is many, the purification difficult of product, and used hypertoxic methyl-sulfate.
Patent WO2007013097 discloses in " synthetic method of ibronate sodium is improved " and has introduced following synthesis technique:
The method methylamine and vinyl cyanide addition reaction, and then with the substitution reaction of bromo pentane silane and 3-methylamino-propionitrile, then hydrolysis obtains final product.The method shortcoming: the 1) product of methylamine and vinyl cyanide addition reaction, because it is sterically hindered little, it can continue and the vinyl cyanide addition reaction, and the reaction more complicated, be difficult to purifying.2) bromo pentane silane can continue to carry out substitution reaction generation quaternary ammonium salt with substitution product 3-[(N-methyl-N-amyl group) amino] propionitrile, can cause the yield degradation like this, and can cause raw material 3-N-methylamino propionitrile reaction incomplete, 3-N-methylamino propionitrile can continue to remain in final product, the separation and purification difficulty.If, in order to guarantee that 3-methylamino-propionitrile thoroughly reacts completely, need to add excessive bromo pentane silane, still, excessive bromo pentane silane can continue to generate quaternary ammonium salt, have a strong impact on yield with the product 3 that generates-[(N-methyl-N-amyl group)] aminopropionitrile reaction.
Summary of the invention:
For above deficiency, the objective of the invention is in order to provide a kind of starting material to be easy to get cheaply, yield is high, and is simple to operate, and product purity is high, is suitable for the preparation method of 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates of large-scale industrial production.
The object of the present invention is achieved like this:
The preparation method of the present invention 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorate, the method is by n-amylamine and acrylate, to carry out the Michael addition reaction to obtain 3-(N-penta amino) ethyl propionates, with formic acid, formaldehyde reaction, obtain 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates again.
The preparation method of the present invention 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorate comprises the following steps:
1) in reactor, add n-amylamine and acrylate, the weight of acrylate is 0.5-20 times of n-amylamine weight, reaction under-10-70 ℃ under stirring, after completion of the reaction, add water, regulate pH to 2-7, obtain organic phase N-penta amino acrylates, with organic solvent extraction, remove excessive acrylate, it is 8-14 that water is adjusted to pH, and organic solvent extraction goes out product, concentrates and does and obtain 3-(N-penta amino) propionic esters;
2) in 3-(N-amylamine base) propionic esters, adding weight is the formaldehyde of 0.5-5 times or the paraformaldehyde of 3-(N-amylamine base) propionic ester weight, and weight is the 3-[formic acid of 0.5-5 times of (N-amylamine base) propionic ester weight, under stirring, under-10-70 ℃, react to TLC and show that 3-(N-amylamine base) propionic ester spots disappear, the TLC reaction is complete, be evaporated to dried, add the hydrochloric acid reflux hydrolysis, TLC hydrolysis fully, is filtered, filtrate being concentrated into done and obtain highly purified 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates.
In above-mentioned step 1), ethyl propenoate weight is 1-2 times of n-amylamine weight, step 2) in, the weight of formaldehyde or paraformaldehyde is 1-2 times of ester weight on 3-(N-amylamine base) propionic acid, and the weight of formic acid is 1-2 times of 3-(N-amylamine base) ethyl propionate weight.
Above-mentioned n-amylamine, acrylate be stirring reaction at room temperature.
Above-mentioned acrylate is vinylformic acid alkane ester or vinylformic acid aromatic ester, vinylformic acid alkane ester is methyl acrylate, ethyl propenoate, propyl acrylate, butyl acrylate, isopropyl acrylate, isobutyl acrylate etc., and the vinylformic acid aromatic ester is phenyl acrylate, benzyl acrylate etc.
Above-mentioned organic solvent is at least a in ethyl acetate, toluene, ether, isopropyl ether, methyl tertiary butyl ether, methylene dichloride, chloroform.
Preparation method's route of the present invention is as follows:
The present invention comprises take n-amylamine and acrylate as starting raw material, preparation N-penta aminopropan acid esters:
The feature of its reactions steps is:
1) select with the n-amylamine that is easy to get on the market, rather than the N-dimethylpentylamine that is difficult to obtain is starting raw material;
2) cheap acrylate wherein, wherein ester refers to alkane esters, for example methyl esters, ethyl ester, propyl ester, butyl ester, isopropyl ester, isobutyl ester etc., or aromatic ester, as phenyl ester, benzyl ester etc., it is the starting raw material that participates in reaction, is also reaction solvent, can guarantee that like this starting raw material amylamine thoroughly reacts completely;
3) in addition, because N-penta aminopropan acid esters steric effect is huge, it can't continue and excessive acrylate reactions.
The present invention also with the formic acid/formaldehyde systems of classics to the upper methyl of amino, avoid using substitution reaction, avoided product to continue to be reacted into quaternary ammonium salt:
The present invention's reaction at room temperature just can be carried out smoothly, and guarantees to go up a methyl.
The inventive method take be easy to get on the market and also cheap acrylate, amylamine, formic acid, formaldehyde as starting raw material.Each step reaction is all classical chemical reaction, and reaction has single-minded and characteristic thoroughly, avoids by product, and the purity of the finished product is high, can reach more than 99%.The present invention has avoided substitution reaction, and for example substitution reaction of bromo pentane silane or methyl iodide has so just avoided amino continuation and bromo pentane silane or iodomethane reaction to generate quaternary amine, has greatly improved yield, and yield can reach more than 85%.Route of the present invention is short, and three step chemical reactions get final product.In addition, reaction conditions gentleness of the present invention, the first two steps chemical reaction can carry out at normal temperatures.
Embodiment:
Embodiment 1:
The embodiment of the present invention is 1 preparation method comprise the following steps:
Synthesizing of 1,3-(N-amylamine base) ethyl propionate:
In the 20L reactor, add the 2L n-amylamine, add ethyl propenoate 3.5L, stirred overnight at room temperature, the TLC raw material reaction is complete, adds 20L water, and dilute hydrochloric acid is regulated pH=3-4, separate organic phase, water is regulated pH=9-10 with 10% solution of potassium carbonate, and with ethyl acetate extraction product 3 times (3L * 3), organic phase merges, the saturated common salt washing is (3L * 1) once, anhydrous sodium sulfate drying, concentrating under reduced pressure is done, and obtains 3-(N--amylamine base) ethyl propionates and directly casts single step reaction;
2, preparation 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates:
Get step gained 3-(N-amylamine base) ethyl propionate 2kg, add formalin 2kg and formic acid solution 2.5kg, under room temperature, reaction is spent the night, TLC reacts completely, concentrating under reduced pressure is done, and adds 6mol/L hydrochloric acid 10L, and 9-10hr refluxes, the TLC hydrolysis fully, filter, filtrate is concentrated does, and obtains white solid 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorate, content is greater than 99%, yield 88%.
Embodiment 2:
The present embodiment is 2 preparation methods comprise the following steps:
Synthesizing of 1,3-(N-amylamine base) ethyl propionate
In the 20L reactor, add the 2L n-amylamine, add ethyl propenoate 1L, 60-70 ℃ of stirrings are spent the night, the TLC raw material reaction is complete, adds 20L water, and dilute hydrochloric acid is regulated pH=2-3, separate organic phase, water is regulated pH=10-11 with 10% solution of potassium carbonate, with ethyl acetate extraction product 3 times (3L * 3), organic phase merges, the saturated common salt washing is (3L * 1) once, anhydrous sodium sulfate drying, and concentrating under reduced pressure is done, obtain 3-(N--amylamine base) ethyl propionates, directly cast single step reaction;
2, preparation 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates:
Get step gained 3-(N-amylamine base) ethyl propionate 2kg, add formalin 10kg and formic acid solution 10kg, under room temperature, reaction is spent the night, TLC reacts completely, concentrating under reduced pressure is done, and adds 6mol/L hydrochloric acid 10L, and 9-10hr refluxes, the TLC hydrolysis fully, filter, filtrate is concentrated does, and obtains white solid 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorate, content is greater than 99%, yield 89%.
Embodiment 3:
The present embodiment is 3 preparation methods comprise the following steps:
Synthesizing of 1,3-(N-amylamine base) ethyl propionate
In the 20L reactor, add the 2L n-amylamine, add ethyl propenoate 20L, under room temperature, stir and spend the night, the TLC raw material reaction is complete, adds 20L water, and dilute hydrochloric acid is regulated pH=4-5, separate organic phase, water is regulated pH=10-11 with 10% solution of potassium carbonate, and with ethyl acetate extraction product 3 times (3L * 3), organic phase merges, the saturated common salt washing is (3L * 1) once, anhydrous sodium sulfate drying, concentrating under reduced pressure is done, and must obtain 3-(N--penta amino) ethyl propionates and directly cast single step reaction.
2, preparation 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates
Get step gained 3-(N-amylamine base) ethyl propionate 2kg, add formalin 4kg and formic acid solution 4kg, the lower reaction that refluxes is spent the night, TLC reacts completely, concentrating under reduced pressure is done, and adds 6mol/L hydrochloric acid 10L, and 9-10hr refluxes, the TLC hydrolysis fully, filter, filtrate is concentrated does, and obtains white solid 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorate, content is greater than 99%, yield 90%.
Embodiment 4:
The present embodiment is 4 preparation methods comprise the following steps:
Synthesizing of 1,3-(N-amylamine base) methyl propionate
In the 20L reactor, add the 2L n-amylamine, add methyl acrylate 20L, under room temperature, stir and spend the night, the TLC raw material reaction is complete, adds 20L water, and dilute hydrochloric acid is regulated pH=4-5, separate organic phase, water is regulated pH=10-11 with 10% sodium carbonate solution, and with dichloromethane extraction product 3 times (3L * 3), organic phase merges, the saturated common salt washing is (3L * 1) once, anhydrous sodium sulfate drying, concentrating under reduced pressure is done, and must obtain 3-(N--penta amino) methyl propionates and directly cast single step reaction.
2, preparation 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates
Get step gained 3-(N-amylamine base) methyl propionate 2kg, add formalin 4kg and formic acid solution 4kg, the lower reaction that refluxes is spent the night, TLC reacts completely, concentrating under reduced pressure is done, and adds 6mol/L hydrochloric acid 10L, and 9-10hr refluxes, the TLC hydrolysis fully, filter, filtrate is concentrated does, and obtains white solid 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorate, content is greater than 99%, yield 87%.
Embodiment 5:
The present embodiment is 5 preparation methods comprise the following steps:
Synthesizing of 1,3-(N-amylamine base) benzyl propionate
In the 20L reactor, add the 2L n-amylamine, add benzyl acrylate 20L, under room temperature, stir and spend the night, the TLC raw material reaction is complete, adds 20L water, and dilute hydrochloric acid is regulated pH=4-5, separate organic phase, water is regulated pH=10-11 with 10% sodium hydroxide solution, and with methyl tertiary butyl ether extracted products 3 times (3L * 3), organic phase merges, the saturated common salt washing is (3L * 1) once, anhydrous sodium sulfate drying, concentrating under reduced pressure is done, and must obtain 3-(N--penta amino) benzyl propionates and directly cast single step reaction.
2, preparation 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates
Get step gained 3-(N-amylamine base) benzyl propionate 2kg, add formalin 4kg and formic acid solution 4kg, the lower reaction that refluxes is spent the night, TLC reacts completely, concentrating under reduced pressure is done, and adds 6mol/L hydrochloric acid 10L, and 9-10hr refluxes, the TLC hydrolysis fully, filter, filtrate is concentrated does, and obtains white solid 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorate, content is greater than 99%, yield 86%.
Above-described embodiment is that foregoing of the present invention is further described, but this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to above-described embodiment.All technology that realizes based on foregoing all belong to scope of the present invention.
Claims (7)
1.3 the preparation method of-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorate, the method is by n-amylamine and acrylate, to carry out the Michael addition reaction to obtain 3-(N-penta amino) propionic esters, with formic acid, formaldehyde reaction, obtain 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates again.
2. the preparation method of 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates as claimed in claim 1 is characterized in that comprising the following steps:
1) in reactor, add n-amylamine and acrylate, the weight of acrylate is 0.5-20 times of n-amylamine weight, reaction under-10-70 ℃ under stirring, after completion of the reaction, add water, regulate pH to 2-7, obtain N-penta amino acrylates, with organic solvent extraction, remove excessive acrylate, water is adjusted to, pH is 8-14, organic solvent extraction goes out product, concentrates and does and obtain 3-(N-penta amino) propionic esters;
2) in 3-(N-amylamine base) propionic esters, adding weight is the formaldehyde of 0.5-5 times or the paraformaldehyde of 3-(N-amylamine base) propionic ester weight, and weight is the 3-[formic acid of 0.5-5 times of (N-amylamine base) propionic ester weight, under stirring, under-10-70 ℃, react to TLC and show that 3-(N-amylamine base) propionic ester spots disappear, the TLC reaction is complete, be evaporated to dried, add the hydrochloric acid reflux hydrolysis, TLC hydrolysis fully, is filtered, filtrate being concentrated into done and obtain highly purified 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates.
3. the preparation method of 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates as claimed in claim 2, it is characterized in that acrylate weight in step 1) is 1-2 times of n-amylamine weight, step 2) in, the weight of formaldehyde or paraformaldehyde is 1-2 times of 3-(N-amylamine base) propionic ester weight, and the weight of formic acid is 1-2 times of 3-(N-amylamine base) propionic ester weight.
4. the preparation method of 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates as claimed in claim 2 or claim 3, is characterized in that at room temperature stirring reaction of n-amylamine, acrylate.
5. the preparation method of 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates as claimed in claim 2 or claim 3, is characterized in that acrylate is vinylformic acid alkane ester or vinylformic acid aromatic ester.
6. the preparation method of 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates as claimed in claim 5, it is characterized in that vinylformic acid alkane ester is methyl acrylate, ethyl propenoate, propyl acrylate, butyl acrylate, isopropyl acrylate, isobutyl acrylate, the vinylformic acid aromatic ester is phenyl acrylate, benzyl acrylate.
7. the preparation method of 3-[(N-methyl-N-amyl group) amino] propionic salt hydrochlorates as claimed in claim 2 or claim 3, is characterized in that organic solvent is at least a in ethyl acetate, toluene, ether, isopropyl ether, methyl tertiary butyl ether, methylene dichloride, chloroform.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4942157A (en) * | 1986-07-11 | 1990-07-17 | Boehringer Mannheim Gmbh | 1-hydroxy-3-(N-methyl-N-propylamino)propane-1,1-diphosphonic acid, pharmaceutical compositions and methods of use |
| CN101048165A (en) * | 2004-10-29 | 2007-10-03 | 霍夫曼-拉罗奇有限公司 | Process for the preparation of ibandronate |
| WO2009093258A2 (en) * | 2008-01-24 | 2009-07-30 | Fleming Laboratories Limited | A new and improved process for the preparation of ibandronate sodium monohydrate |
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- 2013-08-19 CN CN2013103592533A patent/CN103396332A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4942157A (en) * | 1986-07-11 | 1990-07-17 | Boehringer Mannheim Gmbh | 1-hydroxy-3-(N-methyl-N-propylamino)propane-1,1-diphosphonic acid, pharmaceutical compositions and methods of use |
| CN101048165A (en) * | 2004-10-29 | 2007-10-03 | 霍夫曼-拉罗奇有限公司 | Process for the preparation of ibandronate |
| WO2009093258A2 (en) * | 2008-01-24 | 2009-07-30 | Fleming Laboratories Limited | A new and improved process for the preparation of ibandronate sodium monohydrate |
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Application publication date: 20131120 |