CN104341333B - A kind of preparation method of pramiracetam sulfate - Google Patents
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
- C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
Abstract
The present invention relates to a kind of preparation method of pramiracetam sulfate, comprising with DIPEA is starting raw material, obtains intermediate N, N-diisopropyl ethylenediamine through chloro, ammonia solution; Then through acidylate, replacement, salify and refining obtain pramiracetam sulfate, be characterized in that reaction process is safe, controlled; Use raw material and solvent cheap, easily obtain; Organic solvent, very easily recovery, greatly reduce organic discharge, improve environmental friendliness; N-[(2-diisopropylaminoethyl) ethyl]-chlor(o)acetamide intermediate, without separation and purification, simplifies conversion unit, makes operating process have more high-level efficiency.
Description
Technical field
The present invention relates to the preparation of medical compounds, particularly the preparation method of pramiracetam sulfate.
Background technology
Pramiracetam sulfate, structural formula is as follows:
It is developed by Warner-Lambert company of the U.S., and within 1993, first in Italy's listing, successively go on the market in the state such as Argentinian, Australian, French, Japanese, current China does not have raw material and the preparation of these product of import.
Pramiracetam belongs to pyrrolidinone compounds nootropics, is a kind of efficient, cognitive activation agent that low toxicity, tolerance are good, belongs to the cyclic derivatives of γ-aminobutyric acid.Can promote that in brain, ADP changes into ATP, vagusstoff can be promoted to synthesize and the conduction of nervous excitation can be strengthened, there is very strong improvement brain function, hypermnesis, promote the ability of brain dexterity, be applicable to attention that the vascular deterioration relevant with the age or pathology causes and hypomnesis, be particularly useful for gerontal patient.Its activity of clinical trial certificate is 6-13 times of piracetam (piracetam), and the 3-4 being oxiracetam doubly, be 1.25 times of aniracetam, and toxicity is low, better tolerance, can be used for long-term prescription, improves symptom, delays dementia of the Alzheimer type.
In existing disclosed technology, the method about pramiracetam sulfate is as follows:
Document (J.IbanezCatalan, SintesisdeO-[1-(m-trifluorometilfenil)-indazol-3-il]-N-(dialquilaminoalquil)-2-hidroxiamidas, AnalesdeQuimica, 1974, 70 (9-10): mention 733 ~ 737.) with 1, 2-ethylene dibromide is starting raw material, synthesize with ortho position dicarboximide and obtain N-(2-bromotrifluoromethane) phthalic imidine, then using diisopropylamine as nucleophilic reagent, be obtained by reacting N-[(N, N-diisopropylaminoethyl) ethyl] phthalic imidine, then hydrolysis obtains product N, N-diisopropyl ethylenediamine.This reaction is owing to having larger volume as the Diisopropylamine of nucleophile, and sterically hindered effect is unfavorable for that reaction is carried out, and will carry out, severe reaction conditions in tube sealing.
Document (WallsL.P., Researchesinthephenanthridineseries.part III .meso-substitutedderivatives, J.Chem.Soc., 1934:104 ~ 109) in mention with diisopropylaminoethanol be starting raw material, benzene is solvent, sulfur oxychloride is chlorizating agent synthesis N, N-di-isopropyl-2-chloroethyl amine, and is directly used in next step reaction with xylene extraction product.Then add potassium phthalimide backflow, then hydrolysis obtains N, N-diisopropyl ethylenediamine.Although this method overcomes sterically hindered effect, 2-diisopropylaminoethyl monochloroethane itself easily forms inner salt form, and by product increases, separation difficulty, and productive rate is lower.
Document (Peng Zhenyun, N, the improvement of N-diisopropyl ethylenediamine preparation method, Xuzhou Medical College's journal, 1999,19 (40): 273 ~ 274) use stable N instead in, N-diisopropylaminoethyl monochloroethane hydrochloride and potassium phthalimide are in N, condensation in dinethylformamide, then uses hydrazine hydrate hydrazinolysis in ethanol.This method uses N instead, after N-diisopropylaminoethyl monochloroethane hydrochloride, stablize due to it and not easily form inner salt, in the reaction due to the neutralization of potassium phthalimide, N, N-diisopropylaminoethyl monochloroethane constantly dissociates out, with the reaction of another molecule potassium phthalimide, in DMF, phthalic imidine negative ion is very strong nucleophile, so nucleophilic reaction can be carried out smoothly.Its shortcoming high cost, is unfavorable for suitability for industrialized production.
Document [DanielB.Luten, Thepreparationofaminonitrilesandtheirquaternaryammoniumd erivatives, J.Org.Chem., 1938,3 (6): 588 ~ 597] with diisopropylamine, formaldehyde and prussic acid for Material synthesis N, N-di-isopropyl acetonitrile, then obtain N, N-diisopropyl ethylenediamine with sodium borohydride as reductive agent reduction.This method productive rate is high, and its shortcoming prussic acid is violent in toxicity, is difficult to realize industrialization.
In EP2011587, adopt with chloroacetyl chloride and N, N-diisopropyl ethylenediamine in toluene-water two-phase reaction system, make catalyzer with sodium carbonate, synthetic intermediate N-[(2-diisopropylaminoethyl) ethyl]-chlor(o)acetamide.Prepare 2-Pyrrolidone sodium salt with highly basic sodium methylate, then reacting by heating in toluene solution, steam the methyl alcohol generated in reaction, obtain pramiracetam.Feature is that yield is higher.Its weak point needs to prepare 2-Pyrrolidone sodium salt with highly basic sodium methylate, increases single step reaction.We consider that the reaction of this step adopts one kettle way, make catalyzer with sodium hydroxide, can Simplified flowsheet, economize on resources, are beneficial to suitability for industrialized production.
In US4145347, be obtain pramiracetam with pyrrolidone ethyl acetate and the reaction of N, N-diisopropyl ethylenediamine.Its deficiency is in preparation process, and use phase-transfer catalyst TEBA, in reaction process, temperature is too high, and by product is too much.
Based on above some consider, the weak point that the object of the invention is to avoid above-mentioned prior art to exist and provide a kind of simple to operate, reaction conditions is gentle, aftertreatment also relatively simply, the preparation method of the pramiracetam sulfate that reaction safety is high.
Summary of the invention
The preparation method of pramiracetam sulfate provided by the invention, comprising with DIPEA is starting raw material, obtains intermediate N, N-diisopropyl ethylenediamine through chloro, ammonia solution; Then through acidylate, replacement, salify and refining obtain pramiracetam sulfate.
Pramiracetam sulfate provided by the invention and preparation method thereof is represented by following reaction equation:
Pramiracetam sulfate of the present invention and preparation method, comprise the following steps:
(1) preparation of N, N-di-isopropyl-2-chloroethyl amine hydrochloride
Joined by a certain amount of sulfur oxychloride in 50 ~ 100L reactor, under stirring, cryosel bath circulating cooling, controls reactor temperature at 0 ~ 5 DEG C, drips DIPEA, dropwise; Be warming up to 40 ~ 100 DEG C and continue reaction 2 ~ 12h, TLC detection reaction completes.Temperature in the kettle is down to 30 ~ 40 DEG C, under stirring, slowly adds methyl alcohol; Underpressure distillation, obtains red brown solid; Then add single solvent or binary mixed solvent, soak 6h, stir 1h, filter, obtain faint yellow solid wet product; Specified temp and the dry 10h of vacuum under pressure, obtain light yellow product, yield 90%, mp:128.6 ~ 130.9 DEG C.
(2) preparation of N, N-diisopropyl ethylenediamine
Upper step light yellow product is joined in 50 ~ 500L reactor, adds a certain amount of purified water, stir and make it dissolve completely, stand-by.By a certain amount of ammoniacal liquor, join in 500 ~ 3000L reactor, under stirring, controlling reactor internal temperature is 0 ~ 40 DEG C, drips above-mentioned solution, and control to drip speed at 400ml/min, dropwise, continue reaction 8 ~ 16h at such a temperature, now pH is 10 ~ 14.TLC detection reaction completes.With methylene dichloride, 5% sodium hydroxide solution, saturated nacl aqueous solution extraction, filter, 40 ~ 45 DEG C of concentrating under reduced pressure, obtain yellow liquid.Poured into by yellow liquid in 20 ~ 100L matrass, bath temperature 50 ~ 100 DEG C, pressure-0.080 ~-0.099MPa distills, and obtains colourless transparent solution.Yield 50%.
(3) preparation of N-[(2-diisopropylaminoethyl) ethyl]-chlor(o)acetamide
In 100 ~ 500L reactor, add N, N-diisopropyl ethylenediamine, toluene and acid binding agent, stir, make temperature control in it at 0 ~ 50 DEG C, drip chloroacetyl chloride, dropwise, continue reaction 2 ~ 8h, TLC detection reaction completes.With saturated nacl aqueous solution extraction, obtain organic phase solution, carry out next step reaction.
(4) preparation of pramiracetam
2-Pyrrolidone is added, alkali in previous step 50 ~ 500L reactor.25 ~ 80 DEG C of stirring reaction 26h.TLC detection reaction completes.In reaction system, add purified water, extract to obtain aqueous phase, aqueous phase uses dichloromethane extraction again, obtains organic phase, filters; At 40 ~ 45 DEG C of concentrating under reduced pressure, obtain pale yellow oily liquid body, yield 60%.
(5) preparation of pramiracetam sulfate
Pramiracetam is joined in 50 ~ 200L reactor, add solvent, stir and make it dissolve completely; Oil bath circulating cooling, temperature controls at-20 DEG C ~ 40 DEG C, is poured into by ethanol solution of sulfuric acid in above-mentioned 50 ~ 200L reactor, stirring reaction, control temperature is at-20 ~ 40 DEG C, and after 1h, adularescent solid is separated out, continue reaction 4h, white solid is separated out completely, reacts complete.Filter, obtain white filter cake, 55 ~ 60 DEG C of forced air drying 6h, obtain white solid, yield 87%, mp:109.1 ~ 113.0 DEG C.
(6) pramiracetam sulfate is refining
Joined by pramiracetam sulfate in 50 ~ 200L reactor, add solvent, under stirring, 40 ~ 80 DEG C make it dissolve completely.Filter, slow cooling, control temperature is-20 DEG C ~ 20 DEG C stirring and crystallizing, and 5h crystallization is complete, has a large amount of white solid to separate out.Filter, obtain white filter cake, 40 ~ 100 DEG C of forced air drying 6h, obtain white solid, yield 89%, mp:112.5 ~ 114.0 DEG C.
Positively effect of the present invention is, following index is all better than prior art:
(1) reaction process is safe, controlled; Use raw material and solvent cheap, easily obtain;
(2) organic solvent, very easily recovery, greatly reduce organic discharge, improve environmental friendliness;
(3) N-[(2-diisopropylaminoethyl) ethyl]-chlor(o)acetamide intermediate, without separation and purification, simplifies conversion unit, makes operating process have more high-level efficiency;
(4) preparation of N, N-diisopropyl ethylenediamine adopts normal pressure ammonia solution, avoids using expensive catalyzer Raney's nickel to do reaction under high pressure, simplified apparatus, makes reaction process safer controlled.
The method similar with the present invention is J.IbanezCatalan, SintesisdeO-[1-(m-trifluorometilfenil)-indazol-3-il]-N-(dialquilaminoalquil)-2-hidroxiamidas, AnalesdeQuimica, 1974,70 (9-10): the method for 733 ~ 737. documents, the method has following shortcoming:
Employ Diisopropylamine as nucleophile at preparation N, N-diisopropyl ethylenediamine, it has larger volume, and sterically hindered effect is unfavorable for that reaction is carried out, and will carry out, severe reaction conditions in tube sealing.
The method similar with the present invention is WallsL.P., Researchesinthephenanthridineseries.part III .meso-substitutedderivatives, J.Chem.Soc., the method of 1934:104 ~ 109 document, the method has following shortcoming: in preparation process, easily form inner salt by product increase, separation difficulty, productive rate is lower.
The method similar with the present invention is DanielB.Luten.Thepreparationofaminonitrilesandtheirquate rnaryammoniumderivatives.J.Org.Chem., 1938, the method of 3 (6): 588 ~ 597 documents, the method has following shortcoming: in preparation process, use prussic acid, be violent in toxicity, be difficult to realize suitability for industrialized production.
Below by way of tabulated form, advantage of the present invention is described:
Embodiment
Following embodiment is for describing the present invention in detail, and unrestricted the present invention.
Embodiment 1
(1) preparation of N, N-di-isopropyl-2-chloroethyl amine hydrochloride
40.95kg sulfur oxychloride is joined in 100L reactor, mechanical stirring, cryosel bath circulating cooling, reactor temperature is down to 0 ~ 5 DEG C, slowly drips DIPEA 25.00kg, dropwise, be warming up to 75 ~ 80 DEG C of continuation reaction 10h, TLC detection reaction to complete (developping agent: methylene dichloride: methyl alcohol: ammoniacal liquor=20:4:1, iodine develops the color).In reactor during temperature drop to 30 ~ 40 DEG C, under mechanical agitation, slowly add methyl alcohol 5.52kg.Then temperature controls at 55 ~ 60 DEG C, and underpressure distillation, obtains red brown solid; Add ethanol/isopropyl ether (1:10) mixed solvent 22.00kg, 0 ~ 5 DEG C of stirring and crystallizing 10h, dry with whizzer, obtain faint yellow solid wet product; Temperature controls at 55 ~ 60 DEG C, and vacuum-drying 10h obtains pale yellow powder 32.05kg.Yield 93.0%, mp:128.6 ~ 130.9 DEG C.
(2) preparation of N, N-diisopropyl ethylenediamine
Ammoniacal liquor 192.04kg (2406.4mol) is joined in 1000L reactor, mechanical stirring; Bathe circulating cooling with cryosel, make reactor internal temperature be down to 5 ~ 10 DEG C, drip N, N-di-isopropyl-2-chloroethyl amine hydrochloride aqueous solution 160.25kg, continue reaction 8h at such a temperature.TLC detection reaction is (developping agent: methylene dichloride: methyl alcohol: ammoniacal liquor=20:4:1, iodine develops the color) completely.With dichloromethane extraction (141.55kg × 3 time), combined dichloromethane layer solution; Extract once with massfraction 5% sodium hydroxide solution 150kg; Extract once with saturated nacl aqueous solution 150L again, finally use anhydrous sodium sulphate 16.03kg dry methylene chloride layer solution 12h; Filter, 40 ~ 45 DEG C of concentrating under reduced pressure, obtain yellow liquid 19.70kg.Be poured in 50L matrass, bath temperature 90 ~ 100 DEG C, underpressure distillation under pressure-0.098MPa, obtains colourless transparent solution 11.95kg.Yield 51.7%.
(3) preparation of N-[(2-diisopropylaminoethyl) ethyl]-chlor(o)acetamide
N is added in 500L reactor, N-diisopropyl ethylenediamine 11.95kg, toluene 144.95kg and sodium carbonate solution 94.19kg, mechanical stirring, control reactor temperature at 20 ~ 35 DEG C, drip chloroacetyl chloride 11.23kg, dropwise, continue reaction 4h, TLC detection reaction is (developping agent: methylene dichloride: methyl alcohol: ammoniacal liquor=20:4:1, iodine develops the color) completely.Extract once with 50L saturated nacl aqueous solution, leave standstill 30min, separatory.Upper toluene layer stays in a kettle., carries out next step reaction.
(4) preparation of pramiracetam
Pyrrolidone 10.58kg is added, sodium hydroxide 4.97kg in previous step 500L reactor.60 ~ 70 DEG C of mechanic whirl-nett reaction 26h.TLC detection reaction is (developping agent: methylene dichloride: methyl alcohol: ammoniacal liquor=20:4:1, iodine develops the color) completely.In reaction system, add 190.40kg purified water, extraction, obtain aqueous phase, aqueous phase uses dichloromethane extraction (126.20kg × 3 time) again, is merged by dichloromethane layer solution, adds the dry 12h of anhydrous sodium sulphate 9.15kg, filters to get filtrate; 35 ~ 40 DEG C of concentrating under reduced pressure, about need 36h, obtain pale yellow oily liquid body 13.10kg, yield 58.7%.
(5) preparation of pramiracetam sulfate
Joined in 100L reactor by pramiracetam 13.10kg, add dehydrated alcohol 20.00kg, mechanical stirring makes it dissolve completely; Oil bath circulating cooling, temperature controls at 0 ~ 5 DEG C, continues mechanical stirring; Ethanol solution of sulfuric acid 26.15kg is poured in above-mentioned 100L reactor, mechanic whirl-nett reaction; Oil bath circulating cooling, slow cooling, control temperature is at 0 ~ 5 DEG C, and after 1h, adularescent solid is separated out, and continue reaction 4h, white solid is separated out completely, reacts complete.Filter, obtain white filter cake, 55 ~ 60 DEG C of forced air drying 6h, obtain white solid powder 15.70kg, yield 87.9%.mp：109.1～113.0℃
(6) pramiracetam sulfate is refined
Joined in 100L reactor by pramiracetam sulfate 15.70kg, add 37.21kg dehydrated alcohol, under mechanical stirring, back flow reaction makes it dissolve completely.Cooling, control temperature is machinery stirring and crystallizing 0 ~ 5 DEG C time, and 5h crystallization is complete, has a large amount of white solid to separate out.Filter, obtain white filter cake, 55 ~ 60 DEG C of forced air drying 6h, obtain white solid 14.10kg, yield 89.8%.mp：111.9～115.0℃。Detect through HPLC, purity is 99.7%.
Claims (2)
1. a preparation method for pramiracetam sulfate, is characterized in that: comprise the steps:
(1) preparation of N, N-di-isopropyl-2-chloroethyl amine hydrochloride
Sulfur oxychloride slowly drips N after being cooled to 0 ~ 5 DEG C, N-diisopropyl ethanolamine, drip after finishing and be warming up to 75 ~ 80 DEG C, reaction 8 ~ 12h, then 30 ~ 40 DEG C are cooled to, methyl alcohol is added under stirring, underpressure distillation at 55 ~ 60 DEG C, then ethanol/isopropyl ether mixed solvent that volume ratio is 1:10 is added, in 0 ~ 5 DEG C of stirring and crystallizing 10h, filter, in 55 ~ 60 DEG C of vacuum-dryings, obtain N, N-di-isopropyl-2-chloroethyl amine hydrochloride, wherein, N, the mol ratio of N-diisopropyl ethanolamine and sulfur oxychloride is 1.5 ~ 2, methyl alcohol and sulfur oxychloride weight ratio are 0.10 ~ 0.15, the weight ratio of ethanol/isopropyl ether mixed solvent and sulfur oxychloride is 0.4 ~ 0.6,
(2) preparation of N, N-diisopropyl ethylenediamine
N, N-di-isopropyl-2-chloroethyl amine hydrochloride and ammoniacal liquor are in 5 ~ 10 DEG C of contact reacts 6 ~ 10h, add dichloromethane extraction 3 times, respectively extract once with 5% sodium hydroxide solution and saturated nacl aqueous solution again, collected organic layer, with anhydrous sodium sulfate drying, filter, 40-45 DEG C of concentrating under reduced pressure, again in 90 ~ 100 DEG C of underpressure distillation, obtain N, N-diisopropyl ethylenediamine, wherein, N, the mol ratio of N-di-isopropyl-2-chloroethyl amine hydrochloride and ammoniacal liquor is 1:10 ~ 1:20, and the weight ratio of methylene dichloride and N, N-di-isopropyl-2-chloroethyl amine hydrochloride is 4.0 ~ 5.0;
(3) preparation of N-[(2-diisopropylaminoethyl) ethyl]-chlor(o)acetamide
In toluene solvant, chloroacetyl chloride and N, N-diisopropyl ethylenediamine is contact reacts 2 ~ 6h, temperature of reaction 20-35 DEG C under sodium carbonate exists, and adds saturated nacl aqueous solution extraction once, leave and take organic layer, obtain N-[(2-diisopropylaminoethyl) ethyl]-chlor(o)acetamide, wherein, N, the mol ratio of N-diisopropyl ethylenediamine and chloroacetyl chloride is 0.8 ~ 1.0, and the mol ratio of sodium carbonate and chloroacetyl chloride is 0.8 ~ 1.0;
(4) preparation of pramiracetam
Add and pyrrolidone and sodium hydroxide in the final reaction system of previous step, 60 ~ 70 DEG C of reaction 20 ~ 30h, add purified water extraction, leave and take aqueous phase, add dichloromethane extraction 3 times, leave and take organic phase, with anhydrous sodium sulfate drying, filter, 35-40 DEG C of concentrating under reduced pressure, pramiracetam, wherein, pyrrolidone and sodium hydroxide and N-[(2-diisopropylaminoethyl) ethyl]-chlor(o)acetamide mol ratio be 1.0 ~ 2.0;
(5) preparation of pramiracetam sulfate
Mole vitriol oil and pramiracetam will be waited in ethanol in 0 ~ 5 DEG C of contact reacts 2 ~ 6h, and filter, 55-60 DEG C of drying, obtains pramiracetam sulfate crude product;
(6) pramiracetam sulfate is refining
Pramiracetam sulfate crude product is dissolved in ethanol, 0 ~ 5 DEG C of crystallization, and after filtration, 55-60 DEG C of drying, obtains pramiracetam sulfate highly finished product.
2. a preparation method for pramiracetam sulfate, is characterized in that: comprise the steps:
(1) preparation of N, N-di-isopropyl-2-chloroethyl amine hydrochloride
40.95kg sulfur oxychloride is joined in 100L reactor, mechanical stirring, cryosel bath circulating cooling, reactor temperature is down to 0 ~ 5 DEG C, slowly drips N, N-diisopropyl ethanolamine 25.00kg, dropwise, be warming up to 75 ~ 80 DEG C of continuation reaction 10h, TLC detection reaction and complete, its developping agent is: methylene dichloride: methyl alcohol: ammoniacal liquor=20:4:1, develops the color with iodine; In reactor during temperature drop to 30 ~ 40 DEG C, under mechanical agitation, slowly add methyl alcohol 5.52kg, then temperature controls at 55 ~ 60 DEG C, and underpressure distillation, obtains red brown solid; Add the ethanol/isopropyl ether mixed solvent 22.00kg of volume ratio 1:10,0 ~ 5 DEG C of stirring and crystallizing 10h, dry with whizzer, obtain faint yellow solid wet product; Temperature controls at 55 ~ 60 DEG C, and vacuum-drying 10h obtains pale yellow powder 32.05kg;
(2) preparation of N, N-diisopropyl ethylenediamine
Ammoniacal liquor 192.04kg is joined in 1000L reactor, mechanical stirring; Circulating cooling is bathed with cryosel, reactor internal temperature is made to be down to 5 ~ 10 DEG C, drip N, N-di-isopropyl-2-chloroethyl amine hydrochloride aqueous solution 160.25kg, continue reaction 8h at such a temperature, TLC detection reaction is complete, its developping agent is: methylene dichloride: methyl alcohol: ammoniacal liquor=20:4:1, with iodine colour developing, with methylene dichloride 141.55kg/ extraction, extract three times, combined dichloromethane layer solution; Extract once with massfraction 5% sodium hydroxide solution 150kg; Extract once with saturated nacl aqueous solution 150L again, finally use anhydrous sodium sulphate 16.03kg dry methylene chloride layer solution 12h; Filter, 40 ~ 45 DEG C of concentrating under reduced pressure, obtain yellow liquid 19.70kg, are poured in 50L matrass, and bath temperature 90 ~ 100 DEG C, underpressure distillation under pressure-0.098MPa, obtains colourless transparent solution 11.95kg;
(3) preparation of N-[(2-diisopropylaminoethyl) ethyl]-chlor(o)acetamide
N is added in 500L reactor, N-diisopropyl ethylenediamine 11.95kg, toluene 144.95kg and sodium carbonate solution 94.19kg, mechanical stirring, control reactor temperature at 20 ~ 35 DEG C, drip chloroacetyl chloride 11.23kg, dropwise, continue reaction 4h, TLC detection reaction complete, its developping agent is: methylene dichloride: methyl alcohol: ammoniacal liquor=20:4:1, develop the color with iodine, extract once with 50L saturated nacl aqueous solution, leave standstill 30min, separatory, upper toluene layer stays in a kettle., carries out next step reaction;
(4) preparation of pramiracetam
Pyrrolidone 10.58kg is added, sodium hydroxide 4.97kg, 60 ~ 70 DEG C of mechanic whirl-nett reaction 26h in previous step 500L reactor, TLC detection reaction is complete, and its developping agent: methylene dichloride: methyl alcohol: ammoniacal liquor=20:4:1, develops the color with iodine, 190.40kg purified water is added in reaction system, extraction, obtains aqueous phase, and aqueous phase is again with methylene dichloride 126.20kg/ extraction, extract 3 times, dichloromethane layer solution is merged, adds the dry 12h of anhydrous sodium sulphate 9.15kg, filter to get filtrate; 35 ~ 40 DEG C of concentrating under reduced pressure, need 36h, obtain pale yellow oily liquid body 13.10kg;
(5) preparation of pramiracetam sulfate
Joined in 100L reactor by pramiracetam 13.10kg, add dehydrated alcohol 20.00kg, mechanical stirring makes it dissolve completely; Oil bath circulating cooling, temperature controls at 0 ~ 5 DEG C, continues mechanical stirring; To be made into ethanol solution of sulfuric acid 26.15kg with the equimolar sulfuric acid of pramiracetam pours in above-mentioned 100L reactor, mechanic whirl-nett reaction; Oil bath circulating cooling, slow cooling, control temperature is at 0 ~ 5 DEG C, and after 1h, adularescent solid is separated out, and continue reaction 4h, white solid is separated out completely, reacts complete, and filter, obtain white filter cake, 55 ~ 60 DEG C of forced air drying 6h, obtain white solid powder 15.70kg;
(6) pramiracetam sulfate is refined
Pramiracetam sulfate 15.70kg is joined in 100L reactor, add 37.21kg dehydrated alcohol, under mechanical stirring, back flow reaction makes it dissolve completely, cooling, control temperature is machinery stirring and crystallizing 0 ~ 5 DEG C time, and 5h crystallization is complete, has a large amount of white solid to separate out, filter, obtain white filter cake, 55 ~ 60 DEG C of forced air drying 6h, obtain white solid 14.10kg.
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