CN104031002A - Process for synthesizing pramipexole - Google Patents
Process for synthesizing pramipexole Download PDFInfo
- Publication number
- CN104031002A CN104031002A CN201410252075.9A CN201410252075A CN104031002A CN 104031002 A CN104031002 A CN 104031002A CN 201410252075 A CN201410252075 A CN 201410252075A CN 104031002 A CN104031002 A CN 104031002A
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- CN
- China
- Prior art keywords
- acid
- pramipexole
- borohydride
- synthesis technique
- sodium borohydride
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- 0 *[C@@](CC1)*Cc2c1nc(N)[s]2 Chemical compound *[C@@](CC1)*Cc2c1nc(N)[s]2 0.000 description 2
- CDULBSZDCRWJEW-UHFFFAOYSA-N CC(CC(CC1)NS(c(cccc2)c2[N+]([O-])=O)(=O)=O)=C1/N=C(/N)\S Chemical compound CC(CC(CC1)NS(c(cccc2)c2[N+]([O-])=O)(=O)=O)=C1/N=C(/N)\S CDULBSZDCRWJEW-UHFFFAOYSA-N 0.000 description 1
- XCWGJFYDPXSAEW-DAFXYXGESA-N CCCN(C(CC1)CCC(SC2)=C1NC=C2N)S(C1=CC=CC=C[C@@H]1[N+]([O-])=O)(=O)=O Chemical compound CCCN(C(CC1)CCC(SC2)=C1NC=C2N)S(C1=CC=CC=C[C@@H]1[N+]([O-])=O)(=O)=O XCWGJFYDPXSAEW-DAFXYXGESA-N 0.000 description 1
- WVUUEFXYXCGFCN-NTFOPCPOSA-N C[C@@H](CC1)CC2=C1NC(N)S2 Chemical compound C[C@@H](CC1)CC2=C1NC(N)S2 WVUUEFXYXCGFCN-NTFOPCPOSA-N 0.000 description 1
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 invention provides a process for synthesizing pramipexole. The process comprises the following steps: taking S-(-)-2-amino-6-propionamido-4,5-6,7-tetralin benzothiazole as a raw material to restore into free alkali in a reduction reaction system of sodium borohydride or potassium borohydride and fatty acid; and finally generating pramipexole together with an ethyl alcohol salt by the free alkali. The dependence on toxic compounds such as borane or boron fluoride and the like in the traditional craft is cast off by adopting the reduction reaction system of the sodium borohydride or potassium borohydride and the fatty acid, the overall craft process is simple to operate and easy to control, free of toxicity, more environment-friendly, and more beneficial to industrial production, meanwhile, the reduction process is intensively improved by the process disclosed by the invention, side reaction is avoided, and the reaction yield is greatly improved.
Description
[technical field]
The present invention relates to a kind of synthesis technique of pramipexole.
[background technology]
General rope clarke is a kind of Dopamine HCL gaonist, for a new generation's non-ergot class selective dopamine D 2 and D3 receptor stimulant, it can effectively improve Parkinson disease patient's in early stage and late period motor symptoms, alleviate the depressive symptom occur together simultaneously, neuroprotective, delay progression of disease and quality of life is provided; Can also effectively alleviate and alleviate the relevant motor complication of levodopa.Separately (without levodopa) or with levodopa coupling, and drug combination can reduce levodopa consumption.Have easy to use, the feature such as patient tolerability is good.The synthetic method of existing general rope clarke has:
Method one: WO2006070349A2 discloses the method for preparing pramipexole with sodium triacetoxy borohydride reduction, the method is with (S)-2,6-bis-amido-4,5,6,7-tetrahydro benzothiazol is starting raw material, react with positive propionic aldehyde, through sodium triacetoxy borohydride reduction, obtain free alkali again, then through salify, obtain two body of Pramipexole dihydrochloride.
The problem that this preparation method exists is: (1) sodium triacetoxy borohydride is expensive, and process costs is high.(2) propionic aldehyde reaction preference is poor, and easy and 2-amido imide, causes side reaction, and yield is lower.
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-diamino-4, 5, 6, 7-tetrahydro benzothiazol reacts and obtains (S)-N-(2-amino-4 with ortho-nitrophenyl SULPHURYL CHLORIDE in tetrahydrofuran (THF), 5, 6, 7-tetrahydro benzothiazol-6-yl)-2-nitrobenzene sulfonamide, then at salt of wormwood, acetonitrile, (2-amino-4 under N-PROPYLE BROMIDE condition, to obtain (S)-N-, 5, 6, 7-tetrahydro benzothiazol-6-yl)-2-nitro-N-propylbenzene sulphonamide, at salt of wormwood, DMF, under Thiovanic acid condition, obtain (S)-2-amino-6-(N-the third amino) 4, 5, 6, 7-tetrahydro benzothiazol, finally in aqueous ethanolic solution, add the HCl of gaseous state to obtain target compound.
The problem that document preparation method exists is: 1, in reaction, use ortho-nitrophenyl SULPHURYL CHLORIDE, this material is difficult for storing, easy deliquescence, and the large and peculiar smell weight of Thiovanic acid toxicity, is unfavorable for suitability for industrialized production.2, reaction yield is low, and production cost is higher.
Method three: J.Med.Chem.30 (3); 494-498 (1987) discloses a kind of preparation method of general rope clarke dihydrochloride; the method is with S-(-)-2-amino-6-propionamido--4; 5-6; 7-tetrahydro benzothiazol is raw material, in tetrahydrofuran (THF), under logical nitrogen protection, obtains S-(-)-2-amino-6-Propylamino-4 with the borine solution reaction of tetrahydrofuran (THF); 5-6,7-tetrahydro benzothiazol.
There is following shortcoming in the document: the borine 1, using is colourless hypertoxic gas, inflammable, explosive, facile hydrolysis, and poor stability, is difficult for preserving transportation, easily causes security incident, is not suitable for suitability for industrialized production.2, the tetrahydrofuran solution self-control method of borine is complicated, poor repeatability, and the content of the solvent borine that different batches makes is inconsistent, is difficult to industrialization and prepares in a large number.
[summary of the invention]
The technical problem to be solved in the present invention, is to provide a kind of synthesis technique of pramipexole, and this technological 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 synthesis technique for pramipexole, described processing step is as follows:
The first step: reduction reaction
Under agitation in reactor, drop into anhydrous dioxane or tetrahydrofuran (THF), S-(-)-2-amino-6-propionamido--4, 5-6, 7-tetrahydro benzothiazol is raw material, logical nitrogen protection, temperature is controlled at 20-30 ℃, stirring and dissolving, moltenly add sodium borohydride or POTASSIUM BOROHYDRIDE after clear, drip lipid acid, after dropwising, stirring reaction for some time, after heating up, continue stirring reaction, the completely rear purified water that drips of question response, control in still warm at 10-20 ℃, with 10% sodium hydroxide solution, adjust pH to alkalescence, then be extracted with ethyl acetate 3～4 times, merge organic phase, and stir dry 10-12 hour by anhydrous sodium sulphate, filter, by filtrate concentrating under reduced pressure at 40-50 ℃, product is separated out, suction filtration, by product forced air drying 10～12h at 45～50 ℃, obtain free alkali,
Second step: salt-forming reaction
In reactor, drop into free alkali, dehydrated alcohol, heat up, be stirred to molten clearly, after suction filtration, add again water, under agitation drip concentrated hydrochloric acid, naturally cooling, after crystal is separated out, slow cooling, to interior temperature 15-20 ℃, is incubated crystallization 3-4 hour, suction filtration, the quick drip washing of dehydrated alcohol for filter cake, drains rear dryly by convection oven, obtains body of Pramipexole dihydrochloride crude product.
Further, in the described the first step, described acid amides is with the amount of substance of sodium borohydride or POTASSIUM BOROHYDRIDE than being 1:5～10, and described sodium borohydride or POTASSIUM BOROHYDRIDE are 5:1.5～2.5 with the amount of substance ratio of lipid acid.
Further, in the described the first step, described acid amides is with the amount of substance of sodium borohydride or POTASSIUM BOROHYDRIDE than being 1:10, and described sodium borohydride or POTASSIUM BOROHYDRIDE are 3:1 with the amount of substance ratio of lipid acid.
Further, in the described the first step, after described lipid acid need dilute with dioxane or tetrahydrofuran (THF), more slowly drip in reaction solution.
Further, in the described the first step, available lipid acid is acetic acid, propionic acid, isopropyl acid, butyric acid, isopropylformic acid.
Further, the lipid acid in the described the first step is acetic acid.
Further, in the described the first step, with 10-15% sodium hydroxide solution, adjust pH to 12～13.
Tool of the present invention has the following advantages:
What the present invention adopted is sodium borohydride or POTASSIUM BOROHYDRIDE and lipid acid reduction reaction system, than the borine having been reported and boron trifluoride system, makes whole technical process simpler, nontoxicity, more environmental protection; Technique of the present invention does not have other impurity to produce simultaneously, and productive rate has improved greatly.
[embodiment]
The present invention relates to a kind of synthesis technique of pramipexole, described processing step is as follows:
The first step: reduction reaction
Under agitation in reactor, drop into anhydrous dioxane or tetrahydrofuran (THF), S-(-)-2-amino-6-propionamido--4, 5-6, 7-tetrahydro benzothiazol is raw material, logical nitrogen protection, temperature is controlled at 20-30 ℃, stirring and dissolving, moltenly add sodium borohydride or POTASSIUM BOROHYDRIDE after clear, drip lipid acid, after dropwising, stirring reaction for some time, after heating up, continue stirring reaction, the completely rear purified water that drips of question response, control in still warm at 10-20 ℃, with 10% sodium hydroxide solution, adjust pH to alkalescence, then be extracted with ethyl acetate 3～4 times, merge organic phase, and stir dry 10-12 hour by anhydrous sodium sulphate, filter, by filtrate concentrating under reduced pressure at 40-50 ℃, product is separated out, suction filtration, by product forced air drying 10～12h at 45～50 ℃, obtain free alkali,
Second step: salt-forming reaction
In reactor, drop into free alkali, dehydrated alcohol, heat up, be stirred to molten clearly, after suction filtration, add again water, under agitation drip concentrated hydrochloric acid, naturally cooling, after crystal is separated out, slow cooling, to interior temperature 15-20 ℃, is incubated crystallization 3-4 hour, suction filtration, the quick drip washing of dehydrated alcohol for filter cake, drains rear dryly by convection oven, obtains body of Pramipexole dihydrochloride crude product.
In the described the first step, the anhydrous dioxane that every 1g acid amides need drop into or the amount 10～15ml of tetrahydrofuran (THF), described acid amides is with the amount of substance of sodium borohydride or POTASSIUM BOROHYDRIDE than being 1:5～10, and described sodium borohydride or POTASSIUM BOROHYDRIDE are 5:1.5～2.5 with the amount of substance ratio of lipid acid; Preferably, described acid amides is with the amount of substance of sodium borohydride or POTASSIUM BOROHYDRIDE than being 1:10, and described sodium borohydride or POTASSIUM BOROHYDRIDE are 3:1 with the amount of substance ratio of lipid acid.
In the described the first step, after described lipid acid first dilutes with dioxane or tetrahydrofuran (THF), then drip, and dropwised in 50～70 minutes, and every 1ml lipid acid need dilute with 5～10ml dioxane or tetrahydrofuran (THF).
In the described the first step, after lipid acid dropwises, stirring reaction 4h, continues stirring reaction 1h after being warming up to 40 ℃, and question response drips purified water after completely.
Lipid acid in the described the first step is acetic acid, propionic acid, isopropyl acid, butyric acid, isopropylformic acid, is preferably acetic acid.
In the described the first step, with 10-15% sodium hydroxide solution, adjust pH to 12～13.
In the described the first step, the dehydrated alcohol that every 1g free alkali adds is that 3ml, water are that 0.1ml, concentrated hydrochloric acid are 1ml.
Reaction formula 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
Under stirring, drop into anhydrous dioxane 3L, S-(-)-2-amino-6-propionamido--4 in 10L double-layer glass reaction kettle; 5-6; 7-tetrahydro benzothiazol 256g, logical nitrogen protection, is warming up to 20-30 ℃; stirring and dissolving; moltenly add sodium borohydride 216g after clear, drip acetic acid 115g (being diluted in the dioxane of 1L), the about 50-70 minute of time for adding; continue to stir 4 hours, then rise to 40 ℃ of stirrings 1 hour.After reacting completely, drip purified water 5L, the volume ratio of described purified water and reaction solution is approximately 1:1.Control warm 10-20 ℃ in still, with 10% sodium hydroxide solution, adjust pH to 12-13, then use four times (6L*4) of ethyl acetate (EA) extraction, merge organic phase, by 2kg anhydrous sodium sulphate, stir dry 10-12 hour, filter, 40-50 ℃ is evaporated near dry, product is separated out, suction filtration, 45-50 ℃ of forced air drying 10-12 hour.Free alkali 216g detect qualified after for the next step.
Second step: salt-forming reaction
In 2L double-layer glass reaction kettle, drop into free alkali 175g, dehydrated alcohol 525ml, be warming up to interior temperature 25-30 ℃, stir to clarify, after suction filtration, be placed in again double-layer glass reaction kettle, add water 17.5ml, under interior temperature 25-30 ℃ stirring, drip concentrated hydrochloric acid 175ml, reaction nature is warming up to 50-70 ℃, naturally cooling, after crystal is separated out, slow cooling is to interior temperature 15-20 ℃, insulation crystallization 3-4 hour, suction filtration, the quick drip washing of a small amount of dehydrated alcohol for filter cake, drain the dry 10-12 hour of rear 40-45 ℃ convection oven, obtain body of Pramipexole dihydrochloride crude product 162g.
What the present invention adopted is sodium borohydride or POTASSIUM BOROHYDRIDE and lipid acid reduction reaction system, than the borine having been reported and boron trifluoride system, makes whole technical process simpler, nontoxicity, more environmental protection; Technique of the present invention does not have other impurity to produce simultaneously, and productive rate has improved greatly.
Although more than described the specific embodiment of the present invention; but being familiar with those skilled in the art is to be understood that; our described specific embodiment is illustrative; rather than for the restriction to scope of the present invention; those of ordinary skill in the art are in equivalent modification and the variation done according to spirit of the present invention, all should be encompassed in the scope that claim of the present invention protects.
Claims (7)
1. a synthesis technique for pramipexole, is characterized in that: described processing step is as follows:
The first step: reduction reaction
Under agitation in reactor, drop into anhydrous dioxane or tetrahydrofuran (THF), S-(-)-2-amino-6-propionamido--4, 5-6, 7-tetrahydro benzothiazol is raw material, logical nitrogen protection, temperature is controlled at 20-30 ℃, stirring and dissolving, moltenly add sodium borohydride or POTASSIUM BOROHYDRIDE after clear, drip lipid acid, after dropwising, stirring reaction for some time, after heating up, continue stirring reaction, the completely rear purified water that drips of question response, control in still warm at 10-20 ℃, with 10% sodium hydroxide solution, adjust pH to alkalescence, then be extracted with ethyl acetate 3～4 times, merge organic phase, and stir dry 10-12 hour by anhydrous sodium sulphate, filter, by filtrate concentrating under reduced pressure at 40-50 ℃, product is separated out, suction filtration, by product forced air drying 10～12h at 45～50 ℃, obtain free alkali,
Second step: salt-forming reaction
In reactor, drop into free alkali, dehydrated alcohol, heat up, be stirred to molten clearly, after suction filtration, add again water, under agitation drip concentrated hydrochloric acid, naturally cooling, after crystal is separated out, slow cooling, to interior temperature 15-20 ℃, is incubated crystallization 3-4 hour, suction filtration, the quick drip washing of dehydrated alcohol for filter cake, drains rear dryly by convection oven, obtains body of Pramipexole dihydrochloride crude product.
2. the synthesis technique of a kind of pramipexole according to claim 1, it is characterized in that: in the described the first step, described acid amides is with the amount of substance of sodium borohydride or POTASSIUM BOROHYDRIDE than being 1:5～10, and described sodium borohydride or POTASSIUM BOROHYDRIDE are 5:1.5～2.5 with the amount of substance ratio of lipid acid.
3. the synthesis technique of a kind of pramipexole according to claim 2, it is characterized in that: in the described the first step, described acid amides is with the amount of substance of sodium borohydride or POTASSIUM BOROHYDRIDE than being 1:10, and described sodium borohydride or POTASSIUM BOROHYDRIDE are 3:1 with the amount of substance ratio of lipid acid.
4. the synthesis technique of a kind of pramipexole according to claim 1, is characterized in that: in the described the first step, after described lipid acid need dilute with dioxane or tetrahydrofuran (THF), more slowly drip in reaction solution.
5. according to the synthesis technique of a kind of pramipexole described in claim 2～4 any one, it is characterized in that: in the described the first step, available lipid acid is acetic acid, propionic acid, isopropyl acid, butyric acid, isopropylformic acid.
6. the synthesis technique of a kind of pramipexole according to claim 5, is characterized in that: the lipid acid in the described the first step is acetic acid.
7. the synthesis technique of a kind of pramipexole according to claim 1, is characterized in that: in the described the first step, with 10-15% sodium hydroxide solution, adjust pH to 12～13.
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Cited By (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 |
| CN105753812A (en) * | 2016-03-28 | 2016-07-13 | 赤峰赛林泰药业有限公司 | Synthetic method for intermediate of pramipexoledihydrochloride |
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 |
Non-Patent Citations (1)
| Title |
|---|
| NORIHIDE UMINO ET AL.: "Sodium Acyloxyborohydride as New Reducing Agents. I. Reduction of Carboxamides to the corresponding Amines", 《TETRAHEDRON LETTERS》 * |
Cited By (3)
| 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 |
| CN105753812A (en) * | 2016-03-28 | 2016-07-13 | 赤峰赛林泰药业有限公司 | Synthetic method for intermediate of pramipexoledihydrochloride |
| 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 |
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| CN104031002B (en) | 2016-06-22 |
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