CN103012233B - A kind of preparation method of N-(aminothio methyl)-5-oxo-1-propyl group-2-pyrrolidine acetamide - Google Patents
A kind of preparation method of N-(aminothio methyl)-5-oxo-1-propyl group-2-pyrrolidine acetamide Download PDFInfo
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Abstract
The invention discloses the preparation method of a kind of N-(aminothio methyl)-5-oxo-1-propyl group-2-pyrrolidine acetamide, the method uses burnt paddy ammonia alcohol to be starting material, through with Tosyl chloride react generate active ester, then through with the cyaniding of potassium cyanide, N-alkylation with N-PROPYLE BROMIDE, alcoholysis, hydrolysis after obtain 5-(carboxymethyl)-N-propyl group-2-Pyrrolidone, obtain N-(aminothio methyl)-5-oxo-1-propyl group-2-tetramethyleneimine acetyl after reacting with thiocarbamide.Beneficial effect of the present invention: the present invention has prepared the standard substance that purity is greater than the impurity B I-II751XX of 98%.
Description
Technical field
The invention belongs to medicinal chemistry art, relate to the preparation method of a kind of N-(aminothio methyl)-5-oxo-1-propyl group-2-pyrrolidine acetamide.
Background technology
Sen Fuluo (pramipexole) is the first-line treatment medicine of current American Psychiatry disease association, dyskinesia association and various countries' treatment of Parkinson disease Guidelines recommend.Sen Fuluo (body of Pramipexole dihydrochloride sheet) is non-ergot class dopamine-receptor stimulant of new generation, and the main component of this medicine is amino-4,5,6, the 7-tetrahydrochysene-6-propylamine-benzothiazoles (body of Pramipexole dihydrochloride monohydrate) of hydration two hydrochloric acid (S)-2-.Sen Fuluo is mainly used to the S&S for the treatment of idiopathic parkinsonism, and this medicine can be used alone or Dopar (as ceased peaceful, madopar) coupling.Particularly when the curative effect of end-stage disease levodopa weakens gradually or occur change and fluctuate (agent end phenomenon or " switch " fluctuation), in requisition for application this product.
Up-to-date correlative study shows: dopamine agonist---Sen Fuluo (pramipexole), can reduce the danger of the concurrent motor function exception of Parkinsonian, the forfeiture speed of its dopaminergic nerve function that simultaneously can slow down.This shows that pramipexole is hopeful as the Parkinsonian choice drug for the treatment of.This result is reported in the 54th annual meeting of American Psychiatry association.
Sen Fuluo advantageous feature: 1, curative effect is strong: in early days in Parkinsonian as initial treatment, syndrome Control and prevention motor complication these two aspects, the evidence-based medical of Sen Fuluo is the most sufficient.2, high safety: Sen Fuluo, as non-ergot class medicine, there is no the untoward reaction of the valve disorder that clear and definite ergot excitomotor is correlated with at present.3, clinical trial confirms that Sen Fuluo is for intractablely trembling and depressive symptom that PD patient is occurred together also is improved effect of occurring in PD.4, Sen Fuluo absolute bioavailability high (>90%), plasma protein binding ratio low (<20%), liver metabolism limited (not interacting with CYP450), with regard to drug interaction, avoid and affect plasma proteins and be combined or affect the interference between the medicine of CYP450.
In the quality standard of pramipexole, a code name is had to be the degradation impurity of BI-II751XX.The chemistry of this impurity is called N-(aminothio methyl)-5-oxo-1-propyl group-2-pyrrolidine acetamide, and structural formula is as follows:
In order to carry out the quality approach of body of Pramipexole dihydrochloride better, be necessary very much the standard substance obtaining impurity B I-II751XX.But unfortunately, by literature search, the synthesis that we find no about this impurity is reported.
Summary of the invention
The object of this invention is to provide the preparation method of a kind of N-(aminothio methyl)-5-oxo-1-propyl group-2-pyrrolidine acetamide, to synthesize the standard substance of impurity B I-II751XX, carry out the quality approach of body of Pramipexole dihydrochloride better.
The object of the invention is to be achieved through the following technical solutions:
A kind of syntheti c route of N-(aminothio methyl)-5-oxo-1-propyl group-2-pyrrolidine acetamide (BI-II751XX) is as follows:
The preparation method of N-(aminothio methyl)-5-oxo-1-propyl group-2-pyrrolidine acetamide (BI-II751XX), comprises the following steps:
(1) burnt paddy ammonia alcohol and p-methyl benzene sulfonic chloride react and generate 5-(tolysulfonyl ylmethyl)-2-Pyrrolidone (751M-01), add catalyzer DMAP during described burnt paddy ammonia alcohol and p-methyl benzene sulfonic chloride react;
(2) 751M-01 and potassium cyanide back flow reaction generate 5-(cyanogen methyl)-2-Pyrrolidone (751M-02), and the time of reaction is 20 ~ 24 hours;
(3) 751M-02 and N-PROPYLE BROMIDE, under base catalysis, reaction generates 5-(cyanogen methyl)-N-propyl group-2-Pyrrolidone (751M-03), described alkali is sodium hydride, sodium methylate or potassium isopropoxide, preferred sodium cyanide;
(4) 751M-03 and hydrogenchloride-methyl alcohol react and generate 5-(carboxylic methoxycarbonyl)-N-propyl group-2-Pyrrolidone (751M-04), obtain 5-(carboxymethyl)-N-propyl group-2-Pyrrolidone (751M-05) after hydrolysis; And
(5) 751M-05 and thiocarbamide react and generate N-(aminothio methyl)-5-oxo-1-propyl group-2-pyrrolidine acetamide (BI-II751XX), and the mass ratio that feeds intake of thiocarbamide and 751M-05 is 1 ~ 2:1, preferred 1.4:1.
Beneficial effect of the present invention: the present invention has prepared the standard substance that purity is greater than the impurity B I-II751XX of 98%.
Embodiment
The preparation of embodiment one: BI-II751XX
1,5-(tolysulfonyl ylmethyl) synthesis of-2-Pyrrolidone (751M-01)
45g burnt paddy ammonia alcohol is dissolved in 600ml methylene dichloride, add 7.2g DMAP and 60ml triethylamine, stirring at room temperature 15min, add 82.2g Tosyl chloride in batches, heat release in adition process, add complete, stirring at room temperature 14h, TLC monitoring reaction (ethyl acetate: ethanol=4:1, iodine is smoked), treat that raw material reaction is complete, add 400ml methylene dichloride again, add 200ml 1N hydrochloric acid soln again, stir 20min, separatory, the organic layer separated is respectively with 400ml water and the washing of 400ml saturated common salt, add 100g anhydrous sodium sulfate drying, filter, filtrate evaporate to dryness obtains product 102g, yield 97.14%.
2, the synthesis of 5-(cyanogen methyl)-2-Pyrrolidone (751M-02)
By 49.3g5-(tolysulfonyl ylmethyl)-2-Pyrrolidone is dissolved in 400ml acetonitrile, add 29.8g potassium cyanide, reflux 20h, cool to room temperature, leave standstill 3h, supernatant liquor natural filtration, filter cake 200ml acetonitrile washes twice, leave standstill, supernatant liquid filtering, acetonitrile liquid merges, add saturated copperas solution 100ml, stirring at room temperature 1h, filter, filtrate evaporate to dryness, add 400ml acetonitrile stirring at room temperature 1h, filter, filtrate evaporate to dryness, add 100ml toluene, stirred at ambient temperature 1h, separatory, separate lower floor's oil reservoir, add 100ml toluene, stirred at ambient temperature 1h, separate lower floor's oil reservoir, vacuum-drying obtains 5-(cyanogen methyl)-2-Pyrrolidone, yield 55%.
3,5-(cyanogen methyl) synthesis of-N-propyl group-2-Pyrrolidone (751M-03)
5-(cyanogen the methyl)-2-Pyrrolidone of 1g is dissolved in 40ml tetrahydrofuran (THF), adds 0.44g sodium hydride, stirring at room temperature 20min in batches, add 2.2g 1-N-PROPYLE BROMIDE, (developping agent is ethyl acetate in reflux 8h, TLC monitoring reaction, the smoked colour developing of iodine), treat that raw material reaction is complete, cooling, filter, filter cake 60ml tetrahydrofuran (THF) is washed, and filtrate merging weighs, and is spin-dried for, obtain 1.16g oily matter, yield 87.3%.
4,5-(carboxylic methoxycarbonyl) synthesis of-N-propyl group-2-Pyrrolidone (751M-04)
By 1g 5-(cyanogen methyl)-N-propyl group-2-Pyrrolidone 40ml dissolve with methanol, be warming up to 60 DEG C, pass into homemade hydrogen chloride gas, after passing into 1h, stop ventilation, back flow reaction 2h, point plate confirms that (developping agent is sherwood oil to response situation: ethyl acetate=2:1, the smoked colour developing of iodine), as raw material unreacted is complete, then continue ventilation 1h, back flow reaction 2h, rear some plate confirms, repeat this process until raw material complete reaction complete after, solvent evaporated, product 40ml methylene dichloride dissolves, filter, solvent evaporated obtains 0.8g esterification product, yield 57%.
5,5-(carboxymethyl) synthesis of-N-propyl group-2-Pyrrolidone (751M-05)
By 0.8g 5-(carboxylic methoxycarbonyl)-N-propyl group-2-Pyrrolidone 20ml dissolve with methanol, add 4ml water and 2g potassium hydroxide, stirring at room temperature, TLC monitoring reaction (developping agent: pure ethyl acetate, iodine is smoked), after raw material reaction is complete, adding hydrochloric acid to PH is 4, solvent evaporated, obtains 0.64g oily matter, yield 86.4%.
6, the synthesis of N-(amine urea methyl)-5-oxo-1-propyl group-2-ketone pyridineacetamide (BI-II751XX)
By 0.8g 5-(carboxymethyl)-N-propyl group-2-Pyrrolidone is dissolved in 5ml sulfur oxychloride, stirring at room temperature 3h, be dissolved in 10ml acetonitrile after being spin-dried for, be separately dissolved in 20ml acetonitrile by 0.5g thiocarbamide, return stirring is entirely molten to thiocarbamide, drip the acetonitrile solution of acyl chlorides at reflux, drip and finish, maintain back flow reaction state, TLC monitoring reaction (developping agent: methylene dichloride: methyl alcohol=10:1, observable under ultraviolet lamp 254nm, the Rf ≈ 0.75 of product).After question response completes, be spin-dried for solvent, resistates column chromatography (mobile phase dichloromethane: methyl alcohol=20:1) is separated and obtains BI-II751XX, LC-MS:244(M+H), 266(M+Na).
Claims (4)
1. a preparation method for N-(aminothio methyl)-5-oxo-1-propyl group-2-pyrrolidine acetamide, is characterized in that, comprise the following steps:
(1) burnt paddy ammonia alcohol and p-methyl benzene sulfonic chloride are after adding catalyzer DMAP, and reaction generates 5-(tolysulfonyl ylmethyl)-2-Pyrrolidone;
(2) 5-(tolysulfonyl ylmethyl)-2-Pyrrolidone and potassium cyanide back flow reaction generate 5-(cyanogen methyl)-2-Pyrrolidone;
(3) 5-(cyanogen methyl)-2-Pyrrolidone and N-PROPYLE BROMIDE, under base catalysis, reaction generates 5-(cyanogen methyl)-N-propyl group-2-Pyrrolidone, described alkali is sodium hydride, sodium methylate or potassium isopropoxide;
(4) 5-(cyanogen methyl)-N-propyl group-2-Pyrrolidone and hydrogenchloride-methyl alcohol reacts and generates 5-(carboxylic methoxycarbonyl)-N-propyl group-2-Pyrrolidone, obtain 5-(carboxymethyl)-N-propyl group-2-Pyrrolidone after hydrolysis; And
(5) 5-(carboxymethyl)-N-propyl group-2-Pyrrolidone and thiocarbamide react and generate N-(aminothio methyl)-5-oxo-1-propyl group-2-pyrrolidine acetamide.
2. the preparation method according to right 1, is characterized in that: in step (2), and the time of reaction is 20 ~ 24 hours.
3. the preparation method according to right 1, is characterized in that: in step (5), and the mass ratio that feeds intake of thiocarbamide and 5-(carboxymethyl)-N-propyl group-2-Pyrrolidone is 1 ~ 2:1.
4. the preparation method according to right 3, is characterized in that: in step (5), and the mass ratio that feeds intake of thiocarbamide and 5-(carboxymethyl)-N-propyl group-2-Pyrrolidone is 1.4:1.
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| CN114249678A (en) * | 2020-09-21 | 2022-03-29 | 深圳翰宇药业股份有限公司 | Preparation method of N- (aminothiomethyl) -5-oxo-1-propyl-2-pyrrolidine acetamide |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2000012489A1 (en) * | 1998-09-01 | 2000-03-09 | Astrazeneca Ab | 1, 2, 4-triazole-3-thione compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2000012489A1 (en) * | 1998-09-01 | 2000-03-09 | Astrazeneca Ab | 1, 2, 4-triazole-3-thione compounds |
Non-Patent Citations (3)
| Title |
|---|
| Biljana Jancic,等.Experimental design in chromatographic analysis of pramipexole and its impurities.《Acta Chimica Slovenica》.2007,第54卷(第1期),49页表1. * |
| Michael A. Arnold,等.Total Synthesis of (+)-Batzelladine A and (-)-Batzelladine D via [4 + 2]-Annulation of Vinyl Carbodiimides with N-Alkyl Imines.《Journal of the American Chemical Society》.2006,第128卷(第40期),13257页右栏方案5a,倒数第9-12行. * |
| 邢其毅,等.20120570966.X.《基础有机化学》.2005,521,612页. * |
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