CN1884263A - Pregabalin intermediate and process for preparing same - Google Patents
Pregabalin intermediate and process for preparing same Download PDFInfo
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- CN1884263A CN1884263A CNA2005100407288A CN200510040728A CN1884263A CN 1884263 A CN1884263 A CN 1884263A CN A2005100407288 A CNA2005100407288 A CN A2005100407288A CN 200510040728 A CN200510040728 A CN 200510040728A CN 1884263 A CN1884263 A CN 1884263A
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- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/12—Formation of amino and carboxyl groups
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
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- C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
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Abstract
The invention relates to 3-isobutyl glutarimide which is the intermediate of pregabalin treating intermediate and preventing epilepsy, and the method for preparing the same. The method comprises preparation of 3-isobutyl glutarimide by using 3-isobutyl glutaric acid and agent containing nitrogen through cyclocondensation reaction, and preparation of S-(+) - 3- isobutyl gamma- aminobutyric acid through Hoffmann rearrangement and S-amygdalic acid resolution. The method is characterized by simple process, easy separation of intermediate product and end product from reacting dissolvent or recrystallization dissolvent, low cost and suitable for industrial production.
Description
Technical field
The present invention relates to anti-epileptic and treat intermediate of neuralgic medicine lyrica (pregabalin) and preparation method thereof.
Background technology
Compound S-(+)-3-Isobutylgaba (lyrica) is as anti-epileptic and treat neuralgic medicine, uses clinically.The preparation of relevant this compound has many bibliographical informations.
Yuen PW etc. are at Bioorganic ﹠amp; Medicinal Chemistry Letters[1994,4 (6) 823-826] in a kind of method for preparing lyrica is disclosed.Synthetic route is longer, uses butyllithium in reaction, and severe reaction conditions is difficult to realize suitability for industrialized production.
Marvin S.Hoekstra etc. are at Organic Process Research ﹠amp; Development (1997,1, the method of several S-of preparation (+)-3-Isobutylgaba is disclosed 26-38), wherein a method is to adopt 3-isobutyl-pentanedioic acid dehydration condensation, the ammoniacal liquor open loop gets 3-acyl aminomethyl-5-methylhexanoic acid then, after the chiral separation, make lyrica through the Hofmann rearrangement, it is as follows that it closes route:
This method synthetic route is longer relatively, and the fractured operation of intermediate is comparatively cumbersome.Wherein intermediate and chiral separation agent formation transition thing is thick, separates very difficulty from solvent.In addition, the filtration of chiral intermediate, washing must be carried out at low temperatures; And it is bigger to split used solvent-chloroform toxicity.It is synthetic that final step relates to chirality, and the strong basicity that Hoffmann resets makes the intermediate mutarotation that has split, and the lyrica fusing point, the optical purity that obtain are all undesirable.The present application people is according to this method, and the lyrica that makes, fusing point are 176-178 ℃, and chirality HPLC 98%.
Lyrica has been developed to the marketed drug product, presses for a kind of easy and simple to handle, cost efficient, is suitable for scale operation and can guarantees the synthetic method of finished product quality.
Summary of the invention
The technical problem to be solved in the present invention is the method for research and development a kind of S-of preparation (+)-3-Isobutylgaba (lyrica), this method requires (need not special reagent, specific installation, reaction conditions gentleness and do not use the bigger solvent of toxicity) not only easy and simple to handle, product is easily separated (not to have difficult isolating intermediate or end product, intermediate product all easily separates from reaction solvent or recrystallization solvent with end product), cost efficient (use all are raw materials cheap and easy to get), and be suitable for suitability for industrialized production.
The present invention includes a kind of intermediate-3-isobutyl-glutarimide that is used to prepare lyrica.
For addressing the above problem, it is as follows to the invention provides technical scheme.
The 3-isobutyl-glutarimide of formula (I) expression.
Formula (I)
The preparation method of the 3-isobutyl-glutarimide of formula (I) expression comprises and uses 3-isobutyl-pentanedioic acid and nitrogenous reagent through ring-closure reaction.Among this preparation method, nitrogenous reagent is selected from ammoniacal liquor, alkaline ammonium salt, urea, thiocarbamide.3-isobutyl-pentanedioic acid and nitrogenous reagent mol ratio are 1: 1～4; The alkalescence ammonium salt is selected from bicarbonate of ammonia, ammonium acetate; 100～200 ℃ of described ring-closure reaction temperature ranges.
More preferably among the preparation method, 3-isobutyl-pentanedioic acid and nitrogenous reagent mol ratio are 1: 1.5～3; Described ring-closure reaction temperature range to 150～180 ℃; Not low 2 hours ring-closure reaction time; 3-isobutyl-pentanedioic acid and nitrogenous reagent behind ring-closure reaction, the 3-isobutyl-glutarimide C of generation
1～C
5Straight or branched alcohol and water mixing solutions recrystallization.
More in the preferred manufacturing procedure, 3-isobutyl-pentanedioic acid and nitrogenous reagent mol ratio are 1: 2～2.5; C wherein
1～C
5Straight or branched alcohol be selected from methyl alcohol, ethanol, Virahol, propyl carbinol, C
1～C
5The weight part ratio of straight or branched alcohol and water be 2: 1～1: 2.
The purposes of the 3-isobutyl-glutarimide of formula (I) expression in preparation lyrica intermediate 3-isobutyl--γ-An Jidingsuan.
The preparation method of lyrica intermediate 3-isobutyl--γ-An Jidingsuan comprises the steps:
A) 3-isobutyl-pentanedioic acid and nitrogenous reagent make 3-isobutyl-glutarimide (I) at 100～200 ℃ of ring-closure reactions:
B) under the alkaline condition, 3-isobutyl-glutarimide (I) and hypohalite are through the Hofmann rearrangement reaction, and temperature of reaction is 0～100 ℃, with the acid neutralization, make 3-isobutyl--γ-An Jidingsuan then.
The preparation method of described lyrica intermediate 3-isobutyl--γ-An Jidingsuan, wherein
A) nitrogenous reagent is selected from ammoniacal liquor, alkaline ammonium salt, urea, thiocarbamide in the step; 3-isobutyl-pentanedioic acid and nitrogenous reagent mol ratio are 1: 1～4; 150～180 ℃ of described ring-closure reaction temperature ranges; The 3-isobutyl-glutarimide C that ring-closure reaction generates
1～C
5Straight or branched alcohol and water mixing solutions recrystallization;
B) in the step, adding makes their dissolved water, 30～80 ℃ of solvent temperatures, the mol ratio 1: 1～2 of formula (I) compound and alkali in formula (I) compound and alkali; The alkaline solution that will contain formula (I) compound adds in the alkaline aqueous solution of hypohalite, through the Hofmann rearrangement reaction, temperature of reaction is 0～30 ℃, the used amount of hypohalite is calculated as 1～2 times of formula (I) compound by mole number, and hypohalite is selected from sodium hypobromite, clorox, hypoiodous acid sodium; The used alkali of rearrangement reaction is selected from oxyhydroxide, carbonate or the supercarbonate of monovalence or divalent metal; The used acid of acid neutralization is selected from sulfuric acid, hydrochloric acid, acetic acid, oxalic acid.
More preferably among the preparation method of lyrica intermediate 3-isobutyl--γ-An Jidingsuan, ring-closure reaction neutral and alkali ammonium salt is selected from bicarbonate of ammonia, ammonium acetate; 3-isobutyl-pentanedioic acid and nitrogenous reagent mol ratio are 1: 2～2.5, not low 2 hours ring-closure reaction time, the C of recrystallization
1～C
5Straight or branched alcohol be selected from methyl alcohol, ethanol, Virahol, propyl carbinol, C
1～C
5The weight part ratio of straight or branched alcohol and water be 2: 1～1: 2; Used alkali is selected from sodium hydroxide, potassium hydroxide in the Hofmann rearrangement reaction, formula (I) compound is dissolved in 40～60 ℃ of the solvent temperatures of alkali lye, hypohalite is selected from clorox, sodium hypobromite, and sulfuric acid, hydrochloric acid, 10～20 ℃ of rearrangement reaction temperature are selected in the acid neutralization for use.
The present invention makes 3-isobutyl-glutarimide (I) with 3-isobutyl-pentanedioic acid (II) and nitrogenous reagent cyclization at a certain temperature.Nitrogenous reagent can be ammoniacal liquor, bicarbonate of ammonia, ammonium acetate, urea, thiocarbamide, preferred urea.Range of reaction temperature 100-200 ℃, preferred 150-180 ℃.This ring-closure reaction generally will be more than 2 hours, look used nitrogenous dose of difference and difference.
Compound (I) is dissolved in the alkali lye at a certain temperature, and alkali can be oxyhydroxide, carbonate or the supercarbonate of monovalence or divalent metal, preferred sodium hydroxide; 30～80 ℃ of solvent temperatures, preferred 40～60 ℃, solvent temperature is crossed to hang down and is separated the easy open loop of the too high 3-isobutyl-of solvent temperature glutarimide than indissoluble.
Then, the alkaline solution of (I) is splashed in the aqueous solution of hypohalite, at a certain temperature, through Hofmann reset, acid neutralization, recrystallization make 3-Isobutylgaba (III); Used hypohalite can be clorox, sodium hypobromite, hypoiodous acid sodium, preferred clorox, sodium hypobromite (clorox is that commercial, sodium hypobromite is for making by oneself routinely), alkali number is calculated as 1～2 times of hypochlorite in the hypohalite solution by mole number, hypohalite strength of solution weight ratio can be 10～20%; Temperature of reaction 0-100 ℃, preferred 0-30 ℃, most preferably 10-20 ℃; The used acid of acid neutralization can be sulfuric acid, hydrochloric acid, acetic acid, oxalic acid etc., preferably sulfuric acid, hydrochloric acid, most preferably hydrochloric acid.Final compound (III) splits through the S-amygdalic acid and can get that S-(+)-3-Isobutylgaba (lyrica) (IV).
The intermediate of preparation lyrica of the present invention-3-isobutyl-glutarimide is suc as formula shown in (I).
The method for preparing S-(+)-3-Isobutylgaba (lyrica) of the present invention, have three class advantages: 1) this method is easy and simple to handle, need not special reagent, as butyllithium, need not specific installation, as anti-water reactor or low-temp reaction groove etc., reaction conditions gentleness, especially without the bigger solvent of toxicity, as chloroform, benzene; 2) do not have difficult isolating intermediate or end product in the preparation process of the present invention, the gained intermediate product all easily separates from reaction solvent or recrystallization solvent with end product; 3) cost efficient, what the inventive method was used all is raw materials cheap and easy to get.Thereby be suitable for suitability for industrialized production.The present invention includes a kind of new compound 3-isobutyl-glutarimide, it can be used as the intermediate preparation lyrica.
Embodiment:
Help to understand the present invention by following embodiment, but do not limit content of the present invention.
Related raw material and reagent are commercially available among the embodiment, and its specification and source are: isovaleric aldehyde chemical pure Shanghai is to prosperous chemical industry company limited; Ethyl cyanoacetate analytical pure Shanghai chemical reagents corporation; Diethyl malonate chemical pure Shanghai San'aisi Reagent Co., Ltd.; Positive dipropyl amine chemical pure Shanghai is associating chemical industry limited liability company already; Normal hexane analytical pure Shanghai Su Yi chemical reagent company limited; Ammonium acetate chemical pure Shanghai Ling Feng chemical reagent company limited; Ammoniacal liquor (25%) analytical pure Liyang City east chemical reagent company limited; Bicarbonate of ammonia chemical pure Shanghai chemical reagents corporation; Bromine industry Shanghai edifies chemical industry company limited; The urea chemical pure Shanghai Ling Feng chemical reagent S-of company limited (+) amygdalic acid industry one ring Fine Chemical Co., Ltd; Clorox chemical pure Shanghai Ling Feng chemical reagent company limited.
Embodiment one
1) preparation of 3-isobutyl-pentanedioic acid is (with reference to Organic Process Research ﹠amp; Development 1997,1,26-38)
Ethyl cyanoacetate (187.2g, 1.65mol), isovaleric aldehyde (156.3g, 1.81mol) and the 210ml normal hexane, (1.65g 1.62mmol) places reaction flask to positive dipropyl amine, and reflux water-dividing is to anhydrous telling, the concentrating under reduced pressure solvent is to doing, add diethyl phthalate (317.1g, 1.98mol) and positive dipropyl amine (16.8g, 165mmol), 50 ℃ were stirred 1 hour, in the hydrochloric acid of impouring 900ml 6N, refluxed 72 hours the cooling methylbenzene extraction then, extracting solution is concentrated into dried, get 3-isobutyl-pentanedioic acid (261.9g, yield 85%), nucleus magnetic resonance
1HNMR and infrared IR (KBr) are consistent with document.
2) preparation of 3-isobutyl-glutarimide
200.0g (1.06mol) 3-isobutyl-pentanedioic acid and 63.8g (1.06mol) urea are added in the 1000ml there-necked flask.Oil bath is heated to 160 ℃, in 160-180 ℃ of reaction 2 hours, is cooled to 90 ℃ again, directly add entry 400ml under stirring, ethanol 400ml can add gac 15g, reheat refluxed 30 minutes, filtered while hot, filtrate cooling, filtering solution, get crystallization in 50 ℃ of vacuum-dryings, get 3-isobutyl-glutarimide 161g (yield 90%), white plates crystallization, fusing point 137-138 ℃.
Mass spectrum MS:125.9,168.0,168.9.
Nucleus magnetic resonance
1HNMR (CDCl3): δ: 8.01 (s, 1H, exchangable with D2O), 2.72-2.68 (d, 2H), 2.24-2.21 (d, 2H), 1.67-1.62 (m, 2H), 1.28-1.24 (t, 2H), 0.92 (s, 6H).
Infrared IR (KBr): 3198,3088,2955,1735,1686,1422,1384,1291,1269cm-1.
3) preparation of 3-Isobutylgaba
100g (0.59mol) 3-isobutyl-glutarimide, 200ml deionized water and 28.4g (0.71mol) sodium hydroxide are added in the 500ml there-necked flask, and 60 ℃ were stirred 2 hours, and cooled off standby; Again 500g 12% clorox (0.81mol) aqueous solution and 50g sodium hydroxide (1.25mol) are added in the 1000ml there-necked flask, be cooled to 10 ℃, drip above-mentioned reserve liquid, dropwise the back in 10-15 ℃ of stirring reaction 8 hours, as needs, can add sodium bisulfite and remove excessive clorox, concentrated hydrochloric acid is neutralized to pH7, be cooled to 0 ℃, filter, a small amount of washing, use washed with isopropyl alcohol again, use Virahol-water (1: 1) recrystallization at last, can get 3-Isobutylgaba 72.0g (yield 76.6%), fusing point 168-169 ℃.
Nucleus magnetic resonance 1HNMR (D2O): δ: 0.86-0.90 (m, 6H), 1.21 (t, 2H), 1.62-1.69 (m, 1H), 2.12-2.35 (m, 3H), 2.94-3.00 (m, 2H)
Infrared IR (KBr): 2956,2923,2897,2873,2844,2775,2690,2603,2210,1645,1417,1369,1335,1279cm-1
4) preparation of S-(+)-3-Isobutylgaba (lyrica) is (with reference to Organic Process Research ﹠amp; Development 1997,1,26-38)
50g 3-Isobutylgaba and 600ml 3% water-Virahol drop in the reaction flask, add S-(+)-amygdalic acid 75g again, stir, and it is molten entirely to be warming up to solid, is cooled to room temperature then and separates out solid, filter white solid.11g S-(+)-amygdalic acid is dissolved in the above-mentioned white solid of the middle adding of water-Virahol (3%) to be warming up to molten entirely, the water-bath cooling, filter white, needle-shaped crystals, vacuum-drying, S-(+)-3-Isobutylgaba S-(+)-mandelate 32g (mp:132.5-133.5 ℃).This salt is added in the mixed solution of tetrahydrofuran (THF)-water, being warming up to refluxes to make is suspension liquid, and cooling, filtration get white powder.Water-Virahol recrystallization, vacuum-drying gets white crystals 12g,, chirality HPLC 100%, fusing point: 186-187 ℃, and optically-active: [α] D=+10.67 (19 ℃, water).
Embodiment two
1) preparation of 3-isobutyl-pentanedioic acid
With step 1) among the embodiment one
2) preparation of 3-isobutyl-glutarimide
200.0g (1.06mol) 3-isobutyl-pentanedioic acid and 127.7g (2.12mol) urea are added in the 1000ml there-necked flask.Oil bath is heated to 150 ℃, in 150-170 ℃ of reaction 2 hours, is cooled to 80 ℃ again, add entry 200ml, ethanol 400ml and gac 15g, reheat refluxed 30 minutes, filtered while hot, the filtrate cooling, filter, 50 ℃ of vacuum-dryings can get 3-isobutyl-glutarimide 166g (yield 92.3%), the white plates crystallization, fusing point 137-138 ℃.
Mass spectrum MS:125.9,168.0,168.9
Nucleus magnetic resonance 1HNMR (CDCl3): δ: 8.01 (s, 1H, exchangable with D2O), 2.72-2.68 (d, 2H), 2.24-2.21 (d, 2H), 1.67-1.62 (m, 2H), 1.28-1.24 (t, 2H), 0.92 (s, 6H)
Infrared IR (KBr): 3198,3088,2955,1735,1686,1422,1384,1291,1269cm-1
3) preparation of 3-Isobutylgaba
With 100g (0.59mol) 3-isobutyl-glutarimide, 200ml deionized water and 47.2g (1.18mol) sodium hydroxide is added in the 500ml there-necked flask, 40 ℃ were stirred 2 hours, cool off standby, again 728g12% clorox (1.18mol) and 47.2g sodium hydroxide (1.18mol) are added in the 1000ml there-necked flask, be cooled to 5 ℃, drip above-mentioned reserve liquid, dropwise the back in 0-10 ℃ of stirring reaction 10 hours, add sodium bisulfite and remove excessive clorox, concentrated hydrochloric acid is neutralized to pH 7, be cooled to 0 ℃, filter, a small amount of washing, use washed with isopropyl alcohol again, use Virahol-water (1: 1) recrystallization again, can get 3-Isobutylgaba 70.4g (yield 75%), fusing point 168-169 ℃.
Nucleus magnetic resonance 1HNMR (D2O): δ: 0.86-0.90 (m, 6H), 1.21 (t, 2H), 1.62-1.69 (m, 1H), 2.12-2.35 (m, 3H), 2.94-3.00 (m, 2H)
Infrared IR (KBr): 2956,2923,2897,2873,2844,2775,2690,2603,2210,1645,1417,1369,1335,1279cm-1
Embodiment three
1) preparation of 3-isobutyl-pentanedioic acid
With embodiment one. middle step 1)
2) preparation of 3-isobutyl-glutarimide
200.0g (1.06mol) 3-isobutyl-pentanedioic acid and 25% ammoniacal liquor 220g (3.18mol) are added in the 1000ml there-necked flask.(in the experimentation, because ammoniacal liquor is excessive, although volatilization is arranged, but after not influence reaction) concentrated liquor was extremely done, oil bath was heated to 100 ℃, reacts 2 hours, be cooled to 80 ℃ again, add entry 400ml, ethanol 200ml and gac 15g, reheat refluxed 30 minutes, filtered while hot, filtrate cooling, filter, 50 ℃ of vacuum-dryings can get 3-isobutyl-glutarimide 164g (yield 91%), the white plates crystallization, fusing point 137-138 ℃.
Mass spectrum MS:125.9,168.0,168.9
Nucleus magnetic resonance 1HNMR (CDCl3): δ: 8.01 (s, 1H, exchangable with D2O), 2.72-2.68 (d, 2H), 2.24-2.21 (d, 2H), 1.67-1.62 (m, 2H), 1.28-1.24 (t, 2H), 0.92 (s, 6H)
Infrared IR (KBr): 3198,3088,2955,1735,1686,1422,1384,1291,1269cm-1
3) preparation of 3-Isobutylgaba
100g (0.59mol) 3-isobutyl-glutarimide, 200ml deionized water and 28.4g sodium hydroxide (0.71mol) are added in the 500ml there-necked flask, and 50 ℃ were stirred 2 hours, and cooled off standby.Again 300ml deionized water and 80g sodium hydroxide are added in the 1000ml there-necked flask, are cooled to 5-10 ℃, drip 103.8g (0.65mol) bromine, drip off the back and continue to stir 30 minutes.Under 5-10 ℃, drip above-mentioned reserve liquid, dropwised in 2 hours, 10-20 ℃ was stirred 8 hours, neutralize with concentrated hydrochloric acid again, be cooled to 0 ℃, filter, a small amount of washing, use washed with isopropyl alcohol again, use Virahol-water (1: 1) recrystallization again, can get 3-Isobutylgaba 75.2g (yield 80.0%), fusing point 168-169 ℃.
Nucleus magnetic resonance 1HNMR (D2O): δ: 0.86-0.90 (m, 6H), 1.21 (t, 2H), 1.62-1.69 (m, 1H), 2.12-2.35 (m, 3H), 2.94-3.00 (m, 2H)
Infrared IR (KBr): 2956,2923,2897,2873,2844,2775,2690,2603,2210,1645,1417,1369,1335,1279cm-1
Embodiment four
1) preparation of 3-isobutyl-pentanedioic acid
With step 1) among the embodiment one
2) preparation of 3-isobutyl-glutarimide
200.0g (1.06mol) 3-isobutyl-pentanedioic acid, aceticanhydride (water that generates in the decomposition reaction is beneficial to reaction and carries out) 216.2g (2.12mol) and ammonium acetate 163.2g (2.12mol) are added in the 1000ml there-necked flask.After the reflux 4 hours, concentrate and do the excessive aceticanhydride and the acetic acid of generation, be cooled to 90 ℃ again, add entry 400ml, ethanol 400ml and gac 15g, reheat refluxed 30 minutes, filtered while hot, the filtrate cooling, filter, 50 ℃ of vacuum-dryings can get 3-isobutyl-glutarimide 161.8g (yield 90%), the white plates crystallization, fusing point 137-138 ℃.
Mass spectrum MS:125.9,168.0,168.9
Nucleus magnetic resonance 1HNMR (CDCl3): δ: 8.01 (s, 1H, exchangable with D2O), 2.72-2.68 (d, 2H), 2.24-2.21 (d, 2H), 1.67-1.62 (m, 2H), 1.28-1.24 (t, 2H), 0.92 (s, 6H)
Infrared IR (KBr): 3198,3088,2955,1735,1686,1422,1384,1291,1269cm-1
3) preparation of 3-Isobutylgaba
With 100g (0.59mol) 3-isobutyl-glutarimide, 200ml deionized water and 23.6g sodium hydroxide (0.59mol) are added in the 500ml there-necked flask, 80 ℃ were stirred 2 hours, cool off standby, again 364g12% clorox (0.59mol) aqueous solution and 47.2g sodium hydroxide (1.18mol) are added in the 1000ml there-necked flask, be cooled to 5 ℃, drip above-mentioned reserve liquid, dropwise the back in 30-40 ℃ of stirring reaction 8 hours, add sodium bisulfite and remove excessive clorox, concentrated hydrochloric acid is neutralized to pH 7, be cooled to 0 ℃, filter, a small amount of washing, use washed with isopropyl alcohol again, use Virahol-water (1: 1) recrystallization again, can get 3-Isobutylgaba 69.5g (yield 74%), fusing point 168-169 ℃.
Embodiment five
1) preparation of 3-isobutyl-pentanedioic acid
With embodiment one. middle step 1)
2) preparation of 3-isobutyl-glutarimide
100.0g (0.53mol) 3-isobutyl-pentanedioic acid and 167.5g (2.1mol) bicarbonate of ammonia are added in the 1000ml there-necked flask.Oil bath is heated to 200 ℃, reacts 2 hours, is cooled to 90 ℃ again, stir down, add entry 200ml, Virahol 200ml and gac 10g, reheat refluxed 30 minutes, filtered while hot, the filtrate cooling is filtered, 50 ℃ of vacuum-dryings, can get 3-isobutyl-glutarimide 80g (yield 89%), white plates crystallization, fusing point 137-138 ℃.
Mass spectrum MS:125.9,168.0,168.9
Nucleus magnetic resonance 1HNMR (CDCl3): δ: 8.01 (s, 1H, exchangable with D2O), 2.72-2.68 (d, 2H), 2.24-2.21 (d, 2H), 1.67-1.62 (m, 2H), 1.28-1.24 (t, 2H), 0.92 (s, 6H)
Infrared IR (KBr): 3198,3088,2955,1735,1686,1422,1384,1291,1269cm-1.
3) preparation of 3-Isobutylgaba
With 100g (0.59mol) 3-isobutyl-glutarimide, 200ml deionized water and 28.4g sodium hydroxide are added in the 500ml there-necked flask, 80 ℃ were stirred 2 hours, cool off standby, again 500g12% clorox and 50g sodium hydroxide are added in the 1000ml there-necked flask, be cooled to 5 ℃, drip above-mentioned reserve liquid, dropwise the back, add sodium bisulfite and remove excessive clorox in 80-100 ℃ of stirring reaction 5 hours, concentrated hydrochloric acid is neutralized to pH 7, be cooled to 0 ℃, filter, a small amount of washing, use washed with isopropyl alcohol again, use Virahol-water (1: 1) recrystallization again, can get 3-Isobutylgaba 65g (yield 70%), fusing point 168-169 ℃.
Claims (10)
1, the 3-isobutyl-glutarimide of formula (I) expression.
Formula (I)
2, the preparation method of the 3-isobutyl-glutarimide of formula (I) expression comprises and uses 3-isobutyl-pentanedioic acid and nitrogenous reagent through ring-closure reaction.
3, the preparation method of claim 2 is characterized in that: described nitrogenous reagent is selected from ammoniacal liquor, alkaline ammonium salt, urea, thiocarbamide.
4, the preparation method of claim 3 is characterized in that: 3-isobutyl-pentanedioic acid and nitrogenous reagent mol ratio are 1: 1～4; The alkalescence ammonium salt is selected from bicarbonate of ammonia, ammonium acetate; 100～200 ℃ of described ring-closure reaction temperature ranges.
5, the preparation method of claim 4 is characterized in that: 3-isobutyl-pentanedioic acid and nitrogenous reagent mol ratio are 1: 1.5～3; Described ring-closure reaction temperature range to 150～180 ℃; Not low 2 hours ring-closure reaction time; 3-isobutyl-pentanedioic acid and nitrogenous reagent behind ring-closure reaction, the 3-isobutyl-glutarimide C of generation
1～C
5Straight or branched alcohol and water mixing solutions recrystallization.
6, the preparation method of claim 5,3-isobutyl-pentanedioic acid and nitrogenous reagent mol ratio are 1: 2～2.5; C wherein
1～C
5Straight or branched alcohol be selected from methyl alcohol, ethanol, Virahol, propyl carbinol, C
1～C
5The weight part ratio of straight or branched alcohol and water be 2: 1～1: 2.
7, the purposes of the 3-isobutyl-glutarimide of formula (I) expression in preparation lyrica intermediate 3-isobutyl--γ-An Jidingsuan.
8, the preparation method of lyrica intermediate 3-isobutyl--γ-An Jidingsuan comprises the steps:
C) 3-isobutyl-pentanedioic acid and nitrogenous reagent make 3-isobutyl-glutarimide (I) at 100～200 ℃ of ring-closure reactions:
D) under the alkaline condition, 3-isobutyl-glutarimide (I) and hypohalite are through the Hofmann rearrangement reaction, and temperature of reaction is 0～100 ℃, with the acid neutralization, make 3-isobutyl--γ-An Jidingsuan then.
9, the preparation method of claim 8 lyrica intermediate 3-isobutyl--γ-An Jidingsuan, wherein
A) nitrogenous reagent is selected from ammoniacal liquor, alkaline ammonium salt, urea, thiocarbamide in the step; 3-isobutyl-pentanedioic acid and nitrogenous reagent mol ratio are 1: 1～4; 150～180 ℃ of described ring-closure reaction temperature ranges; The 3-isobutyl-glutarimide C that ring-closure reaction generates
1～C
5Straight or branched alcohol and water mixing solutions recrystallization;
B) in the step, adding makes their dissolved water, 30～80 ℃ of solvent temperatures, the mol ratio 1: 1～2 of formula (I) compound and alkali in formula (I) compound and alkali; The alkaline solution that will contain formula (I) compound adds in the alkaline aqueous solution of hypohalite, through the Hofmann rearrangement reaction, temperature of reaction is 0～30 ℃, the used amount of hypohalite is calculated as 1～2 times of formula (I) compound by mole number, and hypohalite is selected from sodium hypobromite, clorox, hypoiodous acid sodium; The used alkali of rearrangement reaction is selected from oxyhydroxide, carbonate or the supercarbonate of monovalence or divalent metal; The used acid of acid neutralization is selected from sulfuric acid, hydrochloric acid, acetic acid, oxalic acid.
10, the preparation method of claim 9 lyrica intermediate 3-isobutyl--γ-An Jidingsuan, ring-closure reaction neutral and alkali ammonium salt is selected from bicarbonate of ammonia, ammonium acetate; 3-isobutyl-pentanedioic acid and nitrogenous reagent mol ratio are 1: 2～2.5, not low 2 hours ring-closure reaction time, the C of recrystallization
1～C
5Straight or branched alcohol be selected from methyl alcohol, ethanol, Virahol, propyl carbinol, C
1～C
5The weight part ratio of straight or branched alcohol and water be 2: 1～1: 2; Used alkali is selected from sodium hydroxide, potassium hydroxide in the Hofmann rearrangement reaction, formula (I) compound is dissolved in 40～60 ℃ of the solvent temperatures of alkali lye, hypohalite is selected from clorox, sodium hypobromite, and sulfuric acid, hydrochloric acid, 10～20 ℃ of rearrangement reaction temperature are selected in the acid neutralization for use.
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| PCT/CN2006/001362 WO2006136087A1 (en) | 2005-06-23 | 2006-06-16 | Preparation method of pregabalin and its intermediate and the said intermediate |
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| WO2011077463A1 (en) * | 2009-12-24 | 2011-06-30 | Msn Laboratories Limited | Process for preparing pregabalin and its intermediate |
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| WO2006136087A1 (en) | 2006-12-28 |
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