CN104031002B - A kind of synthesis technique of pramipexole - Google Patents
A kind of synthesis technique of pramipexole Download PDFInfo
- Publication number
- CN104031002B CN104031002B CN201410252075.9A CN201410252075A CN104031002B CN 104031002 B CN104031002 B CN 104031002B CN 201410252075 A CN201410252075 A CN 201410252075A CN 104031002 B CN104031002 B CN 104031002B
- Authority
- CN
- China
- Prior art keywords
- acid
- pramipexole
- fatty acid
- borohydride
- stirring
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
Abstract
The present invention provides the synthesis technique of a kind of pramipexole, step is as follows: S-(-)-2-amino-6-propionamido--4,5-6,7-tetrahydro benzothiazol is that raw material is reduced into free alkali in sodium borohydride or potassium borohydride and fatty acid reduction reaction system, and free alkali is last becomes salt to generate body of Pramipexole dihydrochloride with ethanol。What the present invention adopted is sodium borohydride or potassium borohydride and fatty acid reduction reaction system, break away from the dependence to the toxic chemical such as borine or boron fluoride in traditional handicraft, made whole technical process simple to operate easy to control, avirulence, more environmental protection, advantageously in industrialized production；Present invention process emphasis improves reducing process simultaneously, it is to avoid produces side reaction, makes reaction yield increase substantially。
Description
[technical field]
The present invention relates to the synthesis technique of a kind of pramipexole。
[background technology]
General rope clarke is a kind of dopamine gaonist; for non-Ergota class selective dopamine D 2 of new generation and D3 receptor stimulating agent; it can effectively improve the motor symptoms of early and late Parkinson disease patient; alleviating the depressive symptom occurred together, protection is neural, delay progression of disease and offer quality of life simultaneously；Can also effectively alleviate and alleviate levodopa-associated motor complication。Can individually (without levodopa) or with levodopa coupling, and drug combination can reduce levodopa consumption。Have easy to use, the features such as patient tolerability is good。The synthetic method of existing general rope clarke has:
Method one: WO2006070349A2 discloses the method preparing pramipexole with sodium triacetoxy borohydride reduction, the method is with (S)-2,6-bis-amido-4,5,6,7-tetrahydro benzothiazols are initiation material, react with positive propionic aldehyde, obtain free alkali then through sodium triacetoxy borohydride reduction, then through becoming salt, obtain two body of Pramipexole dihydrochloride。
This preparation method there is the problem that (1) sodium triacetoxy borohydride is expensive, and process costs is high。(2) propionic aldehyde reaction selectivity is poor, easy and 2-amido imide, causes side reaction, and yield is relatively low。
Method two: CN101622235B discloses the synthetic method of a kind of general rope clarke and pharmaceutically acceptable salt thereof, the method is with (S)-2, 6-diaminourea-4, 5, 6, 7-tetrahydro benzothiazol and ortho-nitrophenyl sulfonic acid chloride are obtained by reacting (S)-N-(2-amino-4 in oxolane, 5, 6, 7-tetrahydro benzothiazol-6-base)-2-nitrobenzene sulfonamide, then at potassium carbonate, acetonitrile, (S)-N-(2-amino-4 is obtained when N-Propyl Bromide, 5, 6, 7-tetrahydro benzothiazol-6-base)-2-nitro-N-propylbenzenesulfonamide, at potassium carbonate, DMF, (S)-2-amino-6-(N-the third amino) 4 is obtained when TGA, 5, 6, 7-tetrahydro benzothiazol, the last HCl adding gaseous state in ethanol water obtains target compound。
Document preparation method there is the problem that 1, uses ortho-nitrophenyl sulfonic acid chloride in reaction, and this material not easily stores, it is easy to deliquescence, and TGA toxicity is big and abnormal flavour weight, is unfavorable for industrialized production。2, reaction yield is low, and production cost is higher。
Method three: J.Med.Chem.30 (3); the preparation method that 494-498 (1987) discloses a kind of general rope clarke dihydrochloride; the method with S-(-)-2-amino-6-propionamido--4; 5-6; 7-tetrahydro benzothiazol is raw material, in oxolane under logical nitrogen protection, react with the Borane solution of oxolane and obtain S-(-)-2-amino-6-Propylamino-4; 5-6,7-tetrahydro benzothiazol。
The borine that the document has the disadvantage in that 1, use is colourless severe toxicity gas, inflammable, explosive, facile hydrolysis, and poor stability not easily preserves transport, it is easy to cause security incident, is not suitable for industrialized production。2, the tetrahydrofuran solution Homemade method of borine is complicated, poor repeatability, and the content of the solvent borine that different batches prepares is inconsistent, it is difficult to industrialization is prepared in a large number。
[summary of the invention]
The technical problem to be solved in the present invention, is in that to provide the synthesis technique of a kind of pramipexole, and this technical process is simple to operate, and toxicity is low, more environmental protection, and synthetic yield is high。
The present invention is achieved in that
A kind of synthesis technique of pramipexole, described processing step is as follows:
The first step: reduction reaction
In reactor, under agitation put into anhydrous dioxane or oxolane, S-(-)-2-amino-6-propionamido--4, 5-6, 7-tetrahydro benzothiazol is raw material, logical nitrogen protection, temperature controls at 20-30 DEG C, stirring and dissolving, molten clear rear addition sodium borohydride or potassium borohydride, dropping fatty acid, after dropwising, stirring reaction a period of time, stirring reaction is continued after intensification, question response drips purified water completely afterwards, control in still warm at 10-20 DEG C, adjust pH to alkaline with 10% sodium hydroxide solution, then 3～4 times it are extracted with ethyl acetate, merge organic facies, and dry 10-12 hour with anhydrous sodium sulfate stirring, filter, by filtrate concentrating under reduced pressure at 40-50 DEG C, product precipitates out, sucking filtration, by product forced air drying 10～12h at 45～50 DEG C, obtain free alkali；
The amount of substance of described amide and sodium borohydride or potassium borohydride is than the amount of substance for 1:5～10, described sodium borohydride or potassium borohydride and fatty acid than for 3:1, and described fatty acid is acetic acid；
Second step: salt-forming reaction
Free alkali, dehydrated alcohol is put in reactor, heating up, stirring is extremely molten clearly, adds water after sucking filtration, under agitation drip concentrated hydrochloric acid, Temperature fall, after crystal precipitates out, slow cooling is to interior temperature 15-20 DEG C, insulation crystallization 3-4 hour, sucking filtration, the quick drip washing of filter cake dehydrated alcohol, dries by convection oven after draining, and obtains body of Pramipexole dihydrochloride crude product。
Further, in the described first step, the amount of substance of described amide and sodium borohydride or potassium borohydride is than for 1:10。
Further, in the described first step, after described fatty acid need to dilute with dioxane or oxolane, then it is slowly added dropwise in reactant liquor。
Further, the fatty acid in the described first step can be selected for as acetic acid, propanoic acid, isopropyl acid, butanoic acid, isopropylformic acid.。
Further, in the described first step, adjust pH to 12～13 with 10-15% sodium hydroxide solution。
Present invention have the advantage that
What the present invention adopted is sodium borohydride or potassium borohydride and fatty acid reduction reaction system, compared to the borine having been reported and boron trifluoride system, makes whole technological process more simply, avirulence, more environmental protection；Present invention process does not have other impurity to produce simultaneously, and productivity substantially increases。
[detailed description of the invention]
The present invention relates to the synthesis technique of a kind of pramipexole, described processing step is as follows:
The first step: reduction reaction
In reactor, under agitation put into anhydrous dioxane or oxolane, S-(-)-2-amino-6-propionamido--4, 5-6, 7-tetrahydro benzothiazol is raw material, logical nitrogen protection, temperature controls at 20-30 DEG C, stirring and dissolving, molten clear rear addition sodium borohydride or potassium borohydride, dropping fatty acid, after dropwising, stirring reaction a period of time, stirring reaction is continued after intensification, question response drips purified water completely afterwards, control in still warm at 10-20 DEG C, adjust pH to alkaline with 10% sodium hydroxide solution, then 3～4 times it are extracted with ethyl acetate, merge organic facies, and dry 10-12 hour with anhydrous sodium sulfate stirring, filter, by filtrate concentrating under reduced pressure at 40-50 DEG C, product precipitates out, sucking filtration, by product forced air drying 10～12h at 45～50 DEG C, obtain free alkali；
Second step: salt-forming reaction
Free alkali, dehydrated alcohol is put in reactor, heating up, stirring is extremely molten clearly, adds water after sucking filtration, under agitation drip concentrated hydrochloric acid, Temperature fall, after crystal precipitates out, slow cooling is to interior temperature 15-20 DEG C, insulation crystallization 3-4 hour, sucking filtration, the quick drip washing of filter cake dehydrated alcohol, dries by convection oven after draining, and obtains body of Pramipexole dihydrochloride crude product。
In the described first step, anhydrous dioxane that every 1g amide need to put into or the amount 10～15ml of oxolane, the amount of substance of described amide and sodium borohydride or potassium borohydride than the amount of substance for 1:5～10, described sodium borohydride or potassium borohydride and fatty acid than for 5:1.5～2.5；Preferably, the amount of substance of described amide and sodium borohydride or potassium borohydride than the amount of substance for 1:10, described sodium borohydride or potassium borohydride and fatty acid than for 3:1。
In the described first step, after described fatty acid first dilutes with dioxane or oxolane, then drip, and dropwised in 50～70 minutes, and every 1ml fatty acid need to be diluted with 5～10ml dioxane or oxolane。
In the described first step, after fatty acid dropwises, stirring reaction 4h, continue stirring reaction 1h after being warming up to 40 DEG C, question response drips purified water completely afterwards。
Fatty acid in the described first step is acetic acid, propanoic acid, isopropyl acid, butanoic acid, isopropylformic acid., is preferably acetic acid。
In the described first step, adjust pH to 12～13 with 10-15% sodium hydroxide solution。
In the described first step, the affiliated dehydrated alcohol of every 1g free alkali is 3ml, water be 0.1ml, concentrated hydrochloric acid is 1ml。
The reaction equation of the present invention is specific as follows:
Below in conjunction with embodiment, the present invention is further illustrated。
Embodiment:
The first step: reduction reaction
In 10L double-layer glass reaction kettle stirring under put into anhydrous dioxane 3L, S-(-)-2-amino-6-propionamido--4; 5-6; 7-tetrahydro benzothiazol 256g, logical nitrogen protection, it is warming up to 20-30 DEG C; stirring and dissolving; the molten clear rear sodium borohydride 216g that adds, dropping acetic acid 115g (being diluted in the dioxane of 1L), time for adding is about 50-70 minute; continue stirring 4 hours, then rise to 40 DEG C of stirrings 1 hour。The volume ratio dripping purified water 5L, described purified water and reactant liquor after reacting completely is approximately 1:1。Control temperature 10-20 DEG C in still, pH to 12-13 is adjusted with 10% sodium hydroxide solution, then four times (6L*4) is extracted by ethyl acetate (EA), merge organic facies, with dry 10-12 hour of 2kg anhydrous sodium sulfate stirring, filter, 40-50 DEG C is evaporated near dry, product precipitates out, sucking filtration, 45-50 DEG C of forced air drying 10-12 hour。Obtain free alkali 216g detection qualified rear for the next step。
Second step: salt-forming reaction
2L double-layer glass reaction kettle puts into free alkali 175g, dehydrated alcohol 525ml, it is warming up to interior temperature 25-30 DEG C, stir to clarify, double-layer glass reaction kettle it is placed in again after sucking filtration, add water 17.5ml, the lower dropping concentrated hydrochloric acid 175ml of interior temperature 25-30 DEG C of stirring, reaction warms naturally to 50-70 DEG C, Temperature fall, after crystal precipitates out, slow cooling is to interior temperature 15-20 DEG C, insulation crystallization 3-4 hour, sucking filtration, the filter cake quick drip washing of a small amount of dehydrated alcohol, drain rear 40-45 DEG C of convection oven dry 10-12 hour, obtain body of Pramipexole dihydrochloride crude product 162g。
What the present invention adopted is sodium borohydride or potassium borohydride and fatty acid reduction reaction system, compared to the borine having been reported and boron trifluoride system, makes whole technological process more simply, avirulence, more environmental protection；Present invention process does not have other impurity to produce simultaneously, and productivity substantially increases。
Although the foregoing describing the specific embodiment of the present invention; but those familiar with the art is to be understood that; we are merely exemplary described specific embodiment; rather than for the restriction to the scope of the present invention; those of ordinary skill in the art, in the equivalent modification made according to the spirit of the present invention and change, should be encompassed in the scope of the claimed protection of the present invention。
Claims (3)
1. the synthesis technique of a pramipexole, it is characterised in that: described processing step is as follows:
The first step: reduction reaction
In reactor, under agitation put into anhydrous dioxane or oxolane, S-(-)-2-amino-6-propionamido--4, 5-6, 7-tetrahydro benzothiazol is raw material, logical nitrogen protection, temperature controls at 20-30 DEG C, stirring and dissolving, molten clear rear addition sodium borohydride or potassium borohydride, dropping fatty acid, after dropwising, stirring reaction a period of time, stirring reaction is continued after intensification, question response drips purified water completely afterwards, control in still warm at 10-20 DEG C, adjust pH to alkaline with 10% sodium hydroxide solution, then 3～4 times it are extracted with ethyl acetate, merge organic facies, and dry 10-12 hour with anhydrous sodium sulfate stirring, filter, by filtrate concentrating under reduced pressure at 40-50 DEG C, product precipitates out, sucking filtration, by product forced air drying 10～12h at 45～50 DEG C, obtain free alkali；
The amount of substance of described amide and sodium borohydride or potassium borohydride is than the amount of substance for 1:5～10, described sodium borohydride or potassium borohydride and fatty acid than for 3:1, and described fatty acid is acetic acid, propanoic acid, isopropyl acid, butanoic acid or isopropylformic acid.；
Second step: salt-forming reaction
Free alkali, dehydrated alcohol is put in reactor, heating up, stirring is extremely molten clearly, adds water after sucking filtration, under agitation drip concentrated hydrochloric acid, Temperature fall, after crystal precipitates out, slow cooling is to interior temperature 15-20 DEG C, insulation crystallization 3-4 hour, sucking filtration, the quick drip washing of filter cake dehydrated alcohol, dries by convection oven after draining, and obtains body of Pramipexole dihydrochloride crude product。
2. the synthesis technique of a kind of pramipexole according to claim 1, it is characterised in that: in the described first step, the amount of substance of described amide and sodium borohydride or potassium borohydride is than for 1:10。
3. the synthesis technique of a kind of pramipexole according to claim 1, it is characterised in that: in the described first step, after described fatty acid need to dilute with dioxane or oxolane, then it is slowly added dropwise in reactant liquor。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410252075.9A CN104031002B (en) | 2014-06-09 | 2014-06-09 | A kind of synthesis technique of pramipexole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410252075.9A CN104031002B (en) | 2014-06-09 | 2014-06-09 | A kind of synthesis technique of pramipexole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104031002A CN104031002A (en) | 2014-09-10 |
| CN104031002B true CN104031002B (en) | 2016-06-22 |
Family
ID=51462023
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410252075.9A Active CN104031002B (en) | 2014-06-09 | 2014-06-09 | A kind of synthesis technique of pramipexole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104031002B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105732539A (en) * | 2014-12-09 | 2016-07-06 | 南京先声东元制药有限公司 | Pramipexole oxidated impurity, preparation and separation method therefor and application of pramipexole oxidated impurity |
| CN105753812B (en) * | 2016-03-28 | 2017-12-08 | 赤峰赛林泰药业有限公司 | The synthetic method of body of Pramipexole dihydrochloride intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1834092A (en) * | 2005-03-15 | 2006-09-20 | 姜能桥 | Prepn. of pramipexole |
| CN101676272A (en) * | 2008-09-17 | 2010-03-24 | 北京德众万全药物技术开发有限公司 | preparation method of pramipexole |
| CN102442972A (en) * | 2011-10-18 | 2012-05-09 | 济南富创医药科技有限公司 | Industrial preparation method for pramipexole and its dihydrochloride monohydrate |
| CN103073519A (en) * | 2012-12-21 | 2013-05-01 | 北京万全德众医药生物技术有限公司 | Method for preparing dextro-pramipexole hydrochloride |
-
2014
- 2014-06-09 CN CN201410252075.9A patent/CN104031002B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1834092A (en) * | 2005-03-15 | 2006-09-20 | 姜能桥 | Prepn. of pramipexole |
| CN101676272A (en) * | 2008-09-17 | 2010-03-24 | 北京德众万全药物技术开发有限公司 | preparation method of pramipexole |
| CN102442972A (en) * | 2011-10-18 | 2012-05-09 | 济南富创医药科技有限公司 | Industrial preparation method for pramipexole and its dihydrochloride monohydrate |
| CN103073519A (en) * | 2012-12-21 | 2013-05-01 | 北京万全德众医药生物技术有限公司 | Method for preparing dextro-pramipexole hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104031002A (en) | 2014-09-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105330609B (en) | A kind of method for preparing LCZ696 | |
| EP3828170A1 (en) | Method for safely preparing pimavanserin and tartrate salt thereof using triphosgene | |
| CN106256824B (en) | Preparation method of high-purity delafloxacin meglumine salt | |
| CN104844488B (en) | A kind of production method of N-acetyl-L-cysteine | |
| CN103724261A (en) | Novel industrial production method for hydroxychloroquine sulfate | |
| CN110551023B (en) | Method for preparing alkyl diacid monobenzyl ester | |
| CN104031002B (en) | A kind of synthesis technique of pramipexole | |
| CN100591649C (en) | Method of preparing R-(+)-3-chlorophenylpropanol | |
| CN103087116A (en) | Sucralose preparation method | |
| CN104193765A (en) | Method for synthesizing cefixime | |
| WO2016202252A1 (en) | Method for synthesizing d-para-hydroxyphenylglycine methyl ester | |
| CN111646998B (en) | Synthesis method of ibrutinib | |
| CN105585539B (en) | The method of one pot process cefotaxime side chain acetoacetic ester | |
| CN103787924A (en) | New purification method of antitumor drug Belinostat | |
| CN104355990B (en) | Method for recycling and mechanically using L- (+) -tartaric acid in D-ethyl ester production | |
| CN107383418B (en) | A kind of uvioresistant plastic additive and preparation method thereof | |
| CN103113294A (en) | Synthesizing method of rebamipide | |
| CN106588921B (en) | A kind of synthetic method of the methyl formate of 7 azaindole 3 | |
| CN105777581A (en) | Cis-1-cyano-4-methoxycyclohexyl-2-(2, 5-dimethylphenyl)acetamide, preparation method and application thereof | |
| CN101857575A (en) | Industrial preparation method of 5-methylpyrazin-2-amine | |
| CN106866560B (en) | Lesinurad synthesis method | |
| CN103896888A (en) | Preparation method of ranitidine bismuth citrate | |
| CN102093254B (en) | Preparation method of 3-(2,2,2-trimethylhydrazine)propionate dihydrate | |
| CN105254650A (en) | Synthesis method of antibacterial drug cefoxitin | |
| CN103992257B (en) | A kind of purification process of Vildagliptin crude product |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |