CN1042904A - The method of preparation (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide - Google Patents

The method of preparation (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide Download PDF

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CN1042904A
CN1042904A CN89108764A CN89108764A CN1042904A CN 1042904 A CN1042904 A CN 1042904A CN 89108764 A CN89108764 A CN 89108764A CN 89108764 A CN89108764 A CN 89108764A CN 1042904 A CN1042904 A CN 1042904A
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ethyl
oxo
alpha
methylthio group
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CN1020604C (en
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高赛门特·埃利克
莫得·日内维夫
杰茨·吉恩-彼勒
格伯特·吉恩
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UCB SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

In NaBH 4/ NiCl 26H 2O, there is hydrogenolysis (S)-α-(2-(methylthio group) ethyl)-2-OXo-1-pyrrolidine yl acetamide preparation (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide down in Raney nickel W-2 or preferred Raney nickel T-1 and so on sweetening agent, and this compound can be used for treatment and prevention central nervous system hypoxgia and the aggressive behaviour of local asphyxia type.

Description

The method of preparation (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide
The present invention relates to the novel method of a kind of preparation (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide, the structural formula of said acid amides is
4,696,943 and 4,837, represent the applicant to introduce above-claimed cpd in No. 223 United States Patent (USP)s, and point out that this compound has the special treatment performance that is different from racemic form that makes it to be all beyond one's expectations with absolute S configuration.Just because of this performance, this S enantiomorph is more suitable for treating and preventing the hypoxgia and the aggressive behaviour of local asphyxia type of central nervous system than racemic form.
In above-mentioned United States Patent (USP) (U.S.4,696,943 and 4,837,223), disclosed the preparation method of (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide.According to these two parts of american documentation literatures, this compound can not adopt the method for separating these two kinds of enantiomers directly to obtain from its racemic mixture.Prepare this compound and must adopt other method, and above-mentioned United States Patent (USP) has specifically been introduced and prepared two kinds of methods that this compound is used.First method is, make successively (S)--ethyl-2-oxo-1-pyrrolidyl acetate is with halo alkyl formate (preferred Vinyl chloroformate) and ammonia react; Second method is to make (S)-4-((1-(aminocarboxyl) propyl group) amino) butyric acid alkyl ester or (S)-N-(1-(aminocarboxyl) propyl group)-cyclisation of 4-halogen butyramide, and these two kinds of compounds itself are prepared by (S)-2-amino-butanamide.
These two kinds of methods all have same shortcoming, all need to prepare the initial reactant that has had suitable three-dimensional chemical configuration.In above-mentioned first method, this initial reactant obtains by taking corresponding racemic compound (±)-alpha-ethyl-2-oxo-1-pyrrolidyl acetate apart, and in the second approach, obtain by taking racemic compound (±)-2-amino-butyramide apart.From corresponding racemic compound, separate when having the enantiomer of required configuration in advance and must make raw materials used loss 50% from the beginning.If consider that reclaiming optically active isomer is difficult to carry out, and then makes the total losses of raw material be far longer than 50% of initial racemic compound under quantitative yield.
Therefore be badly in need of a kind of no above-mentioned shortcoming and operate the method that quite is easy to.
The invention provides a kind of no aforementioned method drawback, thereby the preparation of less expensive (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide method again.And this novel method also has an advantage, promptly uses naturally occurring amino acid L-(methionine(Met)) or its acid amides that obtains easily as initial material.
According to preparation of the present invention (S)-alpha-ethyl-2-oxo-1-pyrrolidyl acetyl with method comprise adopt sweetening agent by following formula to (S)-α-(2-(first methylthio group) ethyl)-2-OXo-1-pyrrolidine yl acetamide carries out hydrogenolysis.
(S)-α-(2-(methylthio group) ethyl)-it is stereospecific that the devulcanization of 2-OXo-1-pyrrolidine yl acetamide is reacted.This reaction generally in water, under the 50-100 ℃ of temperature, sweetening agent (NaBH for example 4/ NiCl 26H 2People such as O(R.B BOAR, chemistry can will, Perkin translates I (1973), 654 pages), Raney nickel W-2 or preferred Raney nickel T-1) exist down, normal pressure or add is depressed people such as (, organic chemistry magazine, 26, (1961 years) 1625 pages) X.DOMINGUEZ and is carried out.
Precursor compound in present method (S)-α-(2-(methylthio group) ethyl)-2-OXo-1-pyrrolidine yl acetamide is a kind of new compound.Can adopt this compound of one of following two methods preparation:
1) making (S)-2-amino-4-(methylthio group) butanamide hydrochloride is with 4-halogen butyryl halogen HalCH 2CH 2CH 2CoHal(wherein Hal is a halogen atom, preferred chlorine atom) react by following formula
Figure 891087648_IMG3
This reaction generally in inert solvent (as methylene dichloride), under about 0 ℃, bromination
Figure 891087648_IMG4
Carry out under fourth ammonium and so on catalyzer exists and under the existence of powder potassium hydroxide.
2) a) make (S)-2-amino-4-(methylthio group earlier) butyramide and-halogen butyric acid alkyl ester XCH 2CH 2CH 2COOR(wherein X is halogen, and R is the alkyl of 1-4 carbon atom), react by following formula:
This reaction general using is in toluene and so on inert solvent, and organic tert-alkali (as triethylamine) and so on acid acceptor exists down and the mode that heated several hours under 80-100 ℃ of temperature is carried out.
B) make a) (S)-4-((1-(the aminocarboxyl)-3-(methylthio group) propyl group that makes in the step then) amino) the butyric acid alkyl ester presses the following formula cyclisation
Figure 891087648_IMG6
This cyclization generally in toluene or dimethylbenzene and so on inert solvent, utilize under the 100-130 ℃ of temperature and the method that heated several hours in the presence of 2 hydroxy pyrimidine and so on the catalyzer carry out.
(S)-2-amino-4-(methylthio group as free alkali) butyramide can by the L-methionine(Met) adopt document (E.SANDRIN and R.A.BOISSONNAS, Helv.Chim.Aeta, 46, (1963), the method for introducing in 1637-1669) is prepared.Fusing point 50-51 ℃, specific rotatory power (α) 22 D=-27.7 ° (C=2, dimethyl formamide).
Can make raw material with this alkali, press people such as A.EBERLE in document (Helv.Chim.Acta, 61, (1978), the method of being introduced 2360-74) prepares known compound (S)-2-amino-4-(methylthio group) butanamide hydrochloride, 212～215 ℃ of fusing points, specific rotatory power [α] 25 D=+26.4 ° (C=1, dimethyl formamide).
The following examples are intended to be used to illustrate the present invention.
In this embodiment, the polarimetry purity of the finished product be the calorimetry by the differential enthalpy measure confirmed (C.FOUQUEY and J.JACQUES, Tetrahedron, 23, (1967), 4009-19).
Embodiment
I. preparation precursor compound (S)-α-(2-(methylthio group) ethyl)-2-OXo-1-pyrrolidine yl acetamide.
1) be raw material with 4-halogen butyryl halogen
Following 84 of room temperature gram anhydrous sodium sulphate be added to by 92.25 grams (0.5 mole) (S)-2-amino-4-(methylthio group) in butyramide and 600 milliliters of methylene dichloride preparations and the suspension.This mixture is cooled to add in succession after 0 ℃ 115 gram powder potassium hydroxide and methylene dichloride (100 milliliters) solution that is dissolved with 8.1 gram (0.025 mole) bromination tetrabutylammoniums.Drip methylene dichloride (100 milliliters) solution that contains 77.5 gram (0.55 mole) 4-chlorobutanoylchlorides in same temperature and under stirring fast.Add 550 milliliters of methylene dichloride between charge period simultaneously and dilute this reaction medium.Stir under 0 ℃ and in this mixture, add 29 gram powder potassium hydroxide after 2 hours.After reaction is carried out four and a half hours, add 29 gram powder potassium hydroxide again and continue stirring 1 hour in 0 ℃.Filter this reaction mixture with Hyflocel then, filtrate is carried out reduction vaporization, residue obtains white powder compound (S)-α-(2-methylthio group) ethyl through silicon oxide chromatogram (with methylene chloride/ammoniacal liquor: 95.5/4.5/0.2(V/V/V) mixture is as elutriant) purifying)-2-OXo-1-pyrrolidine yl acetamide (66 gram), specific rotatory power (α) 25 D=-39.1 ° (C=1, methyl alcohol), productive rate 61%.
To C 9H 16N 2O 2The analysis of S (%):
Calculated value: C 50.00 H 7.41 N 12.96
Observed value: C 50.15 H 7.80 N 12.94
2) be raw material with 4-halogen butyric acid alkyl ester
A) ethyl butyrate amino preparation (S)-4-((1-aminocarboxyl)-3-(methylthio group) propyl group))
In by 10 grams (68 mmole) (S)-2-amino-4-(methylthio group) add 10.57 milliliters of (76 mmole) triethylamines in the suspension of butyramide and the preparation of 100 milliliters of toluene.Stir fast down this mixture heating up to 80-85 ℃ and drip 13.26 and restrain (68 mmole) 4-bromo-butyric acid ethyl esters.Kept this temperature 8 hours, and after the solvent removed by evaporation at reduced pressure, residue was dissolved in 100 milliliters of methylene dichloride.This mixture of reflux 30 minutes, filtered while hot, the residue that evaporate to dryness filtrate obtains obtains 6.2 gram (S)-4-((1-(aminocarboxyl)-3-(methylthio group) propyl group through silicon oxide chromatogram (ethyl acetate/methanol/ammoniacal liquor: 10/0.1/0.1(V/V/V) mixture is made elutriant)) amino) ethyl butyrate, specific rotatory power (α) 25 436=-14.1 ° (C=1, methyl alcohol), productive rate 35%.
This intermediate compound need not be further purified and be directly used in last cyclization.
B) the thick product of 0.6 gram (2.29 milli rub pleasure) and 21.3 milligrams of (0.225 mmole) 2 hydroxy pyrimidines of obtaining in a) step are mixed in 1.15 milliliters of p-Xylol.In nitrogen atmosphere under 130 ℃ with this mixture heating up 4.5 hours.At room temperature it was stirred 30 minutes after the cooling.Leach the precipitation of formation and carry out recrystallization, obtain 0.18 gram (S)-α-((2-methylthio group) ethyl)-2-OXo-1-pyrrolidine yl acetamide, specific rotatory power (α) with ethyl acetate 25 D=-36.5 ° (C=1, methyl alcohol), productive rate 36%.
To C 9H 16N 2O 2The analysis of S (%).
Calculated value: C 50.00 H 7.41 N 12.96
Observed value: C 49.88 H 7.49 N 12.68
II. preparation (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide
In flask at the bottom of one liter of three neck garden, add people such as 50 gram Raney nickel T-1(X.A.DOMINGUEZ in succession, organic chemistry magazine 26, (1961), 1625 pages), 386 ml waters and 7 grams (0.0324 mole) (S)-α-(2-(methylthio group) ethyl)-2-OXo-1-pyrrolidine yl acetamide.With this mixture heating up to 75 ℃, stirred 1 hour under this temperature, filter the back reduction vaporization except that anhydrating, residue (5.3 gram) carries out recrystallization with 60 milliliters of ethyl acetate and obtains 3.87 gram (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamides, fusing point 112-115 ℃, specific rotatory power (α) 25 D=-90 ° (C=1, acetone), productive rate 69%.
To C 8H 14N 2O 2Analysis (%):
Calculated value: C 56.45 H 8.29 N 16.46
Observed value: C 56.30 H 8.42 N 16.18.

Claims (6)

1, the method for a kind of preparation (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide is characterized in that adopting sweetening agent to make (S)-α-(2-(methylthio group)-ethyl)-2-OXo-1-pyrrolidine yl acetamide hydrogenolysis.
2, a kind of method according to claim 1 is characterized in that said sweetening agent is Raney nickel T-1.
3, a kind of method according to claim 1 is characterized in that said sweetening agent is NaBH 4/ NiCl 26H 2O.
4, a kind of method according to claim 1 is characterized in that said sweetening agent is Raney nickel W-2.
5, a kind of according to each method among the claim 1-4, it is characterized in that under 50-100 ℃ of temperature, in water, carrying out said hydrogenolysis.
6, a kind of compound (S)-α-(2-(methylthio group) ethyl)-2-OXo-1-pyrrolidine yl acetamide.
CN89108764A 1988-11-23 1989-11-22 Process for preparation of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide Expired - Fee Related CN1020604C (en)

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GB9319732D0 (en) 1993-09-24 1993-11-10 Ucb Sa Use of (s)-alpha-ethyl-2-oxo-l-pyrrolidineacetamide for the treatment of anxiety
US6107492A (en) * 1998-05-08 2000-08-22 Ucb, S.A. Process for the preparation of levetiracetam
ES2287039T3 (en) 1999-12-01 2007-12-16 Ucb, S.A. A PIRROLIDINACETAMIDE DERIVATIVE FOR THE TREATMENT OF CHRONIC OR NEUROPATHIC PAIN.
GB0004297D0 (en) 2000-02-23 2000-04-12 Ucb Sa 2-oxo-1 pyrrolidine derivatives process for preparing them and their uses
US7132552B2 (en) * 2003-02-03 2006-11-07 Teva Pharmaceutical Industries, Ltd. Process for producing levetiracetam
ES2214147B1 (en) * 2003-02-28 2005-10-01 Farma-Lepori S.A. PROCEDURE FOR OBTAINING AN ANTIEPILEPTIC AGENT.
PL1667967T3 (en) 2003-09-24 2012-11-30 Ucb Pharma Sa Process for preparing 2-oxo-1-pyrrolidine derivatives
CA2488325C (en) 2004-11-22 2010-08-24 Apotex Pharmachem Inc. Improved process for the preparation of (s)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide and (r)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide
AU2006254336B9 (en) 2005-06-01 2013-02-28 Ucb Pharma, S.A. 2 -oxo-I -pyrrolidine derivatives/ processes for preparing them and their therapeutic use on the central nervous system
US8338621B2 (en) 2005-12-21 2012-12-25 Ucb S.A. Process for the preparation of 2-oxo-1-pyrrolidine derivatives
WO2009050735A1 (en) * 2007-10-15 2009-04-23 Lupin Limited A novel polymorph of levetiracetam and a process for its preparation
EP2147911A1 (en) 2008-07-24 2010-01-27 ZaCh System S.p.A. Process for the preparation of levetiracetam
US7939676B2 (en) 2009-09-17 2011-05-10 Zach System S.P.A. Process for the preparation of levetiracetam
KR102461134B1 (en) 2014-01-21 2022-10-28 얀센 파마슈티카 엔.브이. Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use
UA121965C2 (en) 2014-01-21 2020-08-25 Янссен Фармацевтика Нв Combinations comprising positive allosteric modulators or orthosteric agonists of metabotropic glutamatergic receptor subtype 2 and their use

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PT92365A (en) 1990-05-31
KR0157610B1 (en) 1998-11-16
HU896132D0 (en) 1990-02-28
HUT53072A (en) 1990-09-28
CN1020604C (en) 1993-05-12
FI895562A0 (en) 1989-11-22

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