CA1216299A - Process for preparing 4-amino-5-hexenoic acid - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

A process for preparing N,N-dimethyl-2-[5'-oxo-2'-pyrrolidine]ethylamine, or the N-oxide thereof, which comprises reacting 5-oxo-2-pyrrolidine-acetonitrile with hydrogen and dimethylamine in the presence of a palladium catalyst and, when the N oxide is required, oxidizing the N,N-dimethyl-2-[5'-oxo-2'-pyrrolidine]ethylamine product of said reaction. the compounds are useful in the preparation of 5-vinyl-2-pyrrolidinone which can be hydrolysed to 4-amino -5-hexenoic acid.

Description

~ 13 Proces~ for Preparln~
4-Amino -hexenolc Acid The present invention is directed to a novel proce~
ror prepa~lng 4 arnino-5-hexenoic acid and to nov~l 5 interrrledlatcs employed in the proce~s.
4-~mino--5-hexenolc acid (also known as 4-vinyl-4-amlnobutyric acid, ~-vinyl~ aminobutyric ac~d, or "vinyl-GABA") is described in U.S. Patent 3,9~0 9 927. 4-Amino-5-hexenoic acid is an irreversible inhibitor of ~-10 ~minobutyric acid transaminase (GABA-T~ and is~
therefore7 capable of increasing the level Or ~-aminobutyric acid (GABA~ in the CNS. The compound i~
useful for treating disorders associated with depletion of GA~A le~els in the C~S, for example, tardive 15 dyskinesia, schizophrenia, and seizure disorders such as epilepsy. The biochemical and pharmacological effects of 4-ami~o-5-hexenoic acid are described in Lippert et al., Eur. J~ B~ochem.~ 74, 441 ~1977), Metcalf, Blochemical ...
Pharmacology, 28, 1705 (1979), Lippert et al. 7 Brain 20 Research Bulletin, 5, 375 (1980), and Palrreyman et al., Biochemical Pharmacology, 30, 817 (19B1)~
V.S. Patents 4,~78~463 , 4,235,778 , and 4,Z54,204 disclose the preparation of 4-amin~-5-hexenoic acld by reacting a suitable derivative of 2-vinylcycloproparle-25 1,1-dicarboxylic acid with ammonia to rorm a 3-~-31413 ~ carboxy-, carbox~nido 9 or tert-butoxycarbonyl ~-5-v~nyl-2-pyrrolidinone and treatlng the 3~ carboxy-, carboxamido-, or tert-butoxycarbonyl ]-5~vinyl-2 pyrrolidinone with a strong ac~d. The paterJt~ also 5 describe the decarboxylatlon Or a 3-~ carboxy-, carboxamido-, or tert-butoxycarbonyl ~-5-vinyl-2-pyrrolidinone to afford 5--vinyl-~-pyrrolidinone which can then be converted ~ia bromination and dehydrobromination to 5-ethynyl-2-pyrrolidinone which can be hydrolyzed to 10 4-aminohex-5-ynoic acid, 4-Am~nohex-5-ynoic acid is described in U.S~ Patent No. 3,959,356.
In a first process zspect, the presen~ invention provides a process for preparing 5-vinyl-2-pyrrolldinone which comprises:
15 (a) react~ng 5-oxo-2-pyrrolidine-acetonitrile with hydrogen and dimethylamine in the presence o~ a palladi~m catalyst to ~orm N,N-dimethyl-2-~ 5'-oxo-

2'-pyr`rolidine }ethylamine, (b) oxidizin~ N,N-dimethyl 2-C S'-oxo-2'-pyrrolidine ]-ethylamine with an oxidizing agent to produce thecorresponding N-oxide derivative;
(c) pyrolysis ~r the N-oxide derivative to form 5-vinyl-2-pyrrolidinone; and, optionally, ~d) separating N,N-dimethyl-2-[ 5'-oxo-2~-pyrrolidine }-ethylamine by-product from 5-vi~yl-2-pyrrolidinone product.

~-31413 ~2~f~q3~

In a second proccss aspect, the invention provides a process ror preparing 4-amino-5~hexenoic acid which comprises preparing S-vinyl-2-pyrrolldlnone accordi~g to Steps (a)~ (b~, (c), ~nd (d~ as described herci.nabove and 5 then hydrolyzing the 5-vinyl-2--pyrrolidlnone product.
In a ~h~rd process aspect, the ln~ent~on provides a process for preparing 5-Yinyl-2--pyrrolidinone which comprises the pyrolysis of the N-oxide o~ N,N-dimethyl-2-~ 5'-oxo-2'-pyrrolid~ne ]ethylamine and, optionally, lO separating N,N-dimethyl-2-C 5'-oxo-2'-pyrrolidine ]-ethylamine by-product from the 5-vinyl-2-pyrrolidin~nc product.
In a fourth process aspect, the invention provides a process for preparing N,~-dimethyl-2-(5'oxo-2'-15 pyrrolidinone~ethylamine, or the N-oxide thereof9 which comprises reacting 5-oxo-2-pyrrolidineacetonitrile with hydrogen and dimethylam~ne in the presence Or a palladium catalyst, and, when the ~-oxide is required, oxidizing the N`,N-dimethyl-~-[ S'-o~o-2'-pyrolidinone ]ethylamine 20 product Or acid reaction.
The preparation Or N,N-dime~hyl-2-~ 5'-oxo-2'-pyrrolidinone ~ethylamine, the N-oxide thereo~, 5-vinyl-2-pyrrolidinone, and 4-amino-5-hexenoic acid from 5-oxo-2-pyrrolidineacetonitrile i5 depicted schematically below 25 in CHART 1:

~Z16~

CHART __ n< H
O ~ I CH2CN
~, H .
(1) n~ H B
o~ ~~ CH2CH2N ( CH3 ) 2 (2) H o N , 1-0 I CH2~ H2N(CH3)2 .- (3) r~ H D
//~N CH=CH

H

(4) H02 CCH2 CH2 CHCH=CH2 N~2 ~5) ~6~ 31~13 ~ n Step A, 5-oxo 2-pyrr~lid~noncacetonitrile (1~ i~
reacted with hydrogen ~a5 and dlmethyl~unin~ in th~
presence of a palladlum catalyst, such as palladium-on-barium sulfate or palladium-on aluminium oxide tAl~03]
5 produce N,N-dlmethyl-2-~ 5'-oxo-2' pyrrolidine ~-ethylamine (3). Thls reaction ls analogous to that described by Kindler et al., Arch. Pharm., 283, 1~4 (1950). The reaction can be carried out in an inert solvent, pre~erably a (Cl-C6~alkanol or water, at a 10 temperature from about 20 to 100C. Ambient temperature is preferred. The hydrogen gas pressure can range from about one at~osphere to about 20 atmospheres. Two atmospheres are preferred. The reaction time will vary depending upon the temperature and pressure. The product 15 Or the reaction is recovered from the reaction mixture by conventional procedures. A preferred procedure involves filtering the reaction mixture to remove the catalyst, evaporating the solvent from the filtrate to give a residue, and distillating the residue under vacuum. This 20 procedure wlll remove dimeric and trimeric by-products wh~ch interfere with the next step Or the process.
In Step B, N,~-dimethyl-2-~ 5'-oxo-2' pyrrslidine 3 ethylamine (23 is oxid~zed in manner known per se to give the corresponding N-oxide derivative (3). The oxidizlng 25 agent employed in Step B can be ~ny reagent ~nown in the art to be useful for oxidizing a tertiary amlne to the ~-.3141~
~16~

correspondlng N-oxlde derivative. Suitable reagents, conditlons, ~nd solvents for the oxida~ion z~acti~n w~ll be apparent to those skilled in the art~ A prefcrred rea~ent ls hydrogen peroxide in water, for exalnple~ 30%
5 hydrogen peroxide -- water, or in a (Cl-C6)alkanol, for example, methc~nol or ethanol, or mixtures thereo~
Or~anic peracids, such as peracetic acid, performic acid, perbenzoic acid, m-chlQroperbenzoic acid, or perphthalic acid can also be employed. T~e rollowing are examples of 10 solvents that can be used with organic peracids:
tetrahydroruran and chloroform (perbenzoic and m-chloroperbenzoic acid), benzene ~perbenzoic acid), diethyl ether (peracetic acid). Peracetic acid can also be used without an additional solvent. Other oxidizlng 15 agents are In~rganic peracids, ~or example, persulfuric a~id~ and ozone. Persulfur~c acid can be use~ without an additional solvent. Ozone oan be used ~n chloroform or dilute sulfuric acid. For the peracids, the oxidation reaction can be carried out at a temperature ranging from 20 about -5 to about 50~C. Ambient temperature i~ preferred.
For ozone, the reaction can be carried ou~ at -78C. The N-oxide derivatiYe is recovered from the oxldation reac$ion mixture but need not be pur~ed. The recovery of the N-oxide derivative can be accomplishe~ using 25 conventional techniques. For example, when 30~ hydr~gen peroxlde - water ls employed as the oxldlzing agent, ~h~
N-oxide convenlently can be recovered by treating the reaction mixture with platiniwn black or cataluse (or other suitable peroxide - destroying rca~ent) k~ destroy 5 excess hydrogen peroxide, filtering the mixture, extracting the filtrate with chloroform, separating the aqueous phase, and evaporating solvent from the aqueous phase to give the N-oxide der-ivative as a residue.
In Step C, the N-oxide derivative (3) formed in Step 10 B undergoes the Cope elimination to afford 5-vinyl-2-pyrrolidinone (4~. The elimination is accomplished in manner known ~r se by pyrolysis of the N-oxide deri~ative. Usually the pyrolysis ~ill be carried out at a temperature of at least 140C under reduced pressure~
15 Suitably the temperature o~ the pyrolysis reaction can range fro~ about 140 to about 185C, preferably 150~C~
Conveniently the pyrolysis can be carried out dry under reduced prèssure so that the product, S-vinyl-~-pyrrolidinone, will continuously di~til from the reaction 20 mixture. The elimination reaction may be accompanied by a deoxygenation reaction whereby N~N-dimethyl-2-~ ~'-oxo-2'-pyrrolidine ~ethylamine is produced as a by-product~
When the pyr~lysis is carried out under reduced pressure, the by-product can distil rrom the reaction mixture along ~ 3~413 ~6~

wlth ~-vinyl-2-pyrrolidinone. Ir ~ 1 desired ~o separate the by-product, an aqueou~ ~olut~on Or the clistillate can b~: treated with a suI'ricierlt arnount vr an acidic lon exchc~n~e resin, such as Amberl~te XR 120, ~
5 rorm, untll the æolution show~ a neutral p~, whereby the basic by-product becomes bound to the acidic resin and i8 effectively removed from solution containing the desired product. The resin conta~ning the by-product and any unreacted resin can ~hen be separated rrom the solution 10 by filtratio~.. The neutral aqueous ~iltrate can be used directly in Step D or it can be further treated in manner kno~n per se in order to recover 5-vinyl-2-pyrrolldinone, The rPco~ery of 5-vinyl-2-pyrrolidinone can be accomplished by evaporatlng sol~ent from the neutral 15 filtrate to gi~e a residuer and distilling the residue under vacuum. 5-Yinyl-2-pyrrolidinone thus obtained can be re-dissolved in water, and the resultin~ solution can be subsequently used in Step D.
~f desired7 the resin which is removed by filtration 20 can be treated ln known menner so as t~ regenerate N,N-dimethyl-2-[ 5'-oxo-2'-pyrrolidine ~ethylamine (2), which can then be recycled in Step B.
Other methods known in the art~ such as chromato~raphy, can be used~ lf desired~ to separate the 2~ by-product.

* Trade Mark ~-31413 ~Z~6~
_ g In Ste~_~, 5-vlnyl-2-pyrrolidlnone (4~ is hydro1yxed in known manner per se to ~iYe the desired rinal prod~ct, 4-amlno-5-hexeno~c acld (S). Conditions for openlng th0 lactam ring by acid hydrolysis are well known in the art.
5 For ex~nple, a ~rong acid7 such as hydrochloric acid, or trirluoroacetlc ac~d, can be added to an a~ue~us solution Or 5-vinyl-2-pyrrolidinone (ror example, as obtained from Step C3 and the resulting soiut~on can be heated, prefera~ly above 60C. A most preferred hydrolysiæ
10 procedure is to heat 5-vinyl-2-pyrrolidinone in 5~
aqueous hydrochloric acid at a temperature Or 95 to 100C.
In the acid hydrolysis performed in Step D, 4-amino-S-he~enoic acid forms an acid addition salt with 15 the strong acid present in the reaction medit~. The acid addition salt can be isolated as a residue a~ter evaporating solvent rrom the reaction medium. The residue can be puri~led by conventional means~ such as recrystallizationO If deslred, 4-amino-5-hexenoic acid in 20 *he form of the free base or zwitterion can be obtalned by contacting the ac~d additio~ salt with a strong base~
The ~ree base or zwitterion thus fo~med can be isolated by conventional means. For example, when $he hydrolysis of 4-amino-5-hexenoic acid is carried out using 5%
25 hydrochloric acid, the residue obtained after evaporation ~ z~ t~-31413 o~ solvent from the reaction mediuM is dlssolv~d in ethanol/isopropanol~ triethylam~ne 1~ added to th~
resulting solution tv pH 7 B, and the procluct is separated by precip.itatlon. The precipitate can be 5 purified by d:lssolving it in water, heating the resulting solution wi.kh charcoal (90JC), flltering the mixture, and adding ethanol and isopropanol to the filtrate. Pure 4-amino-5-hexenoic acid will crystallize upon standing at 5C~a 10CHART 2, set forth below, depicts an appropriate method for preparing 5-oxo-2-pyrrolidine-acetonitrile ~1) 9 which is the starting material employed in the proeess o~ this invention [ See CHART 1, Step A, Compound (1~ ].

.

Ho2cc~2cH2~Hco2H2 E

~5) 2~ _ R2CCH2CH2CHC2R2 _ F
NH~

(6 2~-31 413 i~3~3 r C~2~ G ~
H

(7) ~< H
0~ I CH~OH
H

(~) .
-I ~ H
oI ~C}120y H
(9) ., I -I

H
(l~

In CHART 2r R is (C:l~C6~allcyl group and -OY i~
toluenest~ onyloxy ~tosyloxy) or methanesulfonyloxy 25 (mesyloxy).

- ~-31413 ~6~

~ 12 -In S_ep E9 L or DL-~lut~nic acid (5) i5 esteri~ied in known m~nner to ~i~e the dlester (6~. Any conYentlonal esterific~tion method cc~n ~e used. For ex~rlpl~, L or DL-~lutamic acid (5) can be treated with ~hionyl chloride 5 and eth2~01 to g~ve diethyl ~lutc~mate.
In S ep F, the diester (6) undergoes a cyclization reaction to ~ive a pyroglutamic ac~d es~er (7). The cyclization is accomplished in known manner by pyrolysis.
The temperature of the pyrolysis can range from about 150 10 to 200C. It is preferred to carry out the pyrolysis wider reduced pressure so that the pyroglutamic acid ester (7) eontinuously distils from the reaction mixture.
In Step G, the pyroglutamic acid ester ~7) ~
reduced to give ~-hydroxymethyl-2-pyrrolidinone ~8). The 15 reduction conditions employed must be capable of reducing the ester carbonyl without reducing the lactam car~onyl .
Suitable reducing agents are lithlum borohydride in tetrahydrof~ran9 sodium borohydride in water or ethan~l~
or DIBAL-H. Sodium borohydride in water or ethanol is 20 preferred.
In Step H~ 5-hydro~ymethyl-2-pyrrolidinone (8) is converted in known manner to the corresponding tosyloxy or mesyloxy derivative (9)~ One method ls to treat 5-hydroxymethyl-2-pyrrolidinone with tosylchloride or 25 mesylchloride in dry pyridinen Another method for ~ '3~3 l~~31~13 car~ying out the transrormation inv~lves reactlng 5-hydroxymethyl-2-pyrrolidinone with to~ylchlor.1de or mesylchloride ~d sodium hydroxide in rnethylenc chloride/
w~ter in the presence Or a phase kransreI cataly~ uch 5 as tetra-n-butyl~nmon~uM hyclro~len sulrat~.
___ _ , In Step I, the tosyloxy or mesyloxy derivative ~9 is converted in known manner to 5-oxo-2-pyrrolidine-acetonitrile (1)~ The conversion can be accomplished by treating the tosyloxy or mesyloxy derivative (9) with 10 sodium cyanide and sod~um iodide in dry dimethyl-formam~de. 5-Oxo~2-pyrrolidine-acetonitrile must be obtained free Or sodium cyanide to avoid interferences during Step A o~ the subse~uent reaction se~uence.
Since 4-amino-5-hexenoic acid possesses a chiral 15 center, opt~cal isomers are possible ~ and 4-amino-5-hexenoic.acid and the intermediates thereto sh~wn in CHART 1 can exist in the form of a pure enantiomer or a mixture of enantiomer~7 such as the racemate. As will be recognized by those sk~ lled in the art~ the processes Or 20 this in~ention can be employed to maXe each ~ubstantially pure ~ndi~idual enantiomer or the racemate o~ 4-amino-5~
hexenoic acid, or of the intermediates thereto, depending upon the optical configuration of 5-oxo-2-pyrrolidine-acetonitrile, which is used as the starting material Or 25 the over-all process (See Step A, CEIART l~. The starting M-3~4i3 materials and the intermediatcs and product~ produce~
there~rom by the proccss deplcted in CHAR~ 1 are ~o~rn below:

5 Startin~ ater~al In~errnediate~ Product (Com~ound 1~ (Compounds 2, 3, and 4) (Compound 5) . . ~

(S)-5-oxo--2- (S~-N,N-dimethyl-2- (S~-4--amino-pyrrolidine- ~5'-oxo-29-pyrrolidine] 5-hexenoic 10 acetonitrile ethylamine; the ~T-oxide acid thereof; and ~S)-5-vinyl-2-pyrrolidinone (R,S)-5-oxo-2- (R,S~-N,~-dimethyl-2- (R9S~ 4-15 pyrrolidine- ~5'-oxo-2'-pyrrolidine~ amino-5-acetonitrile ethylamine; the N-oxide hexenoic thereof; and (S)-5- acid ~ vinyl-2-pyrrolidinone 20 (R)-5-oxo-2- ~R)-N,~-dime$hyl-2- ~R)-4-amino-pyrrolidine- [5'~oxo-2l~pyrrolidine~ 5-hexenoic acetonitrile ethylamine; the N-oxide acid thereof; and (S)~5-vinyl-2-pyrrolldinone M-31~13 ~6Z~39 1~ has been found that the blologically active enantiGmer Or ~4)-~mino-5-hexenoic acid is the (~
enantiorner, which is (S)-4-amino-S-hexenoi~ aci~ Thl~s, ~he pure blo~oElcally active (S)-cnantiomer or the 5 r~ccmate (l.e. the R,S-form~ o~ ~mino~5-hexenolc acid can be employed in vivo to ~nhibit GABA-T e~zyme. The biologically inac~ive ~R?-enantiorrler o~ 4-arnino-5-hexenoic acid can be converted, however7 in rnanner kno~m ~r se to the (R)-en~ntiomer of 4-aminohex-5-ynoic acld.

_ 10 The method for preparing (R)-4-aminohex-5-ynoic acid from ~R~-4-~mino-5-hexenoic acid ~s illustrated in Examples 10 to 13. The conversion of 5-vinyl-2-pyrrolidinone to 4-aminohex-5-ynoic acid Yia 5-ethynyl-2-pyrrolidinone is also described i~ U.S~ Patent No~ 4,178,463.
The biochemical and pharmacological ef~ects of 4-aminohex-5-ynoic acid are described in Jung et al., Biochem~ and Biophys. Res. Comm., _ ~ 301 (1975), Jung e al.~ J. ~eurochemistry~ 28~ 717 (1977); Jung e al., Biochemlstry~ 17, 2628 (1978); Bouclier _ al., Eur. J.
20 Biochem., 98, 363 (1979)~ Biochem. Pharmacology, 28, 1705 (1979); and Lippert et al., Brain Research Bull.~ 5~ 375 (1980). It has been reported by Lippert et al., supra and Bouclier et al.~ supra, that the (~) enantiomer o~ 4-aminohex~5-ynoic acid~ which is (S)-4-aminohex-5-ynoic 25 acid, ls the on~y en~ntiomer o~ 4-an,inohex-5-ynolc acid ~2~6~9~ M-31413 ~hich will irreversibly inhibit GABA-T. Mor(~ recent expe~iments have demonstrated, howeYer, th~ the ~R~-enantio~er is c~n irreversible inhibitor o~ GABA-'r both ln ViYo and in vl tr_ For ex~mple, t~ ~~nlrlolle~-5-Yt1~ic 5 acld gave the ~ollow effects on G~B~-T activity and GABA
concentrations in mice brain using the test method o~
J~g et al., J~ Neurochernistry, supra:

% Inhibition GABA Concentration 10 Dose (mg~kg) of GABA-T Sa) % Control (a~
control 0 100 5~ 1~5 100 ~ 180 200 8~ 27~

(a) 4 hours a-fter in~ectiorl o~ the test compound, ~.p..

In a c~ronic experiment9 a group of five rats was 20 given oral daily doses o~ lnO mg~kg Or (R)-4-aminohex-5-yno~c acid~ A separate group of animals was used as co~trol. Twenty-four hours after the last dose, the animals were sacri~iced and the cortex was dissected ~rom the rest Or the brain. GABA-T activity was measured in 25 homogenates Or brain minus the eortex and was found to ~ M-31413 ~6~

be decreased by 81~ ln the an~mals treated with (~)-4-aminohex-5-ynoic acid as compared to con~rol~. r;A~A
concentrat~on was measured in homogenates of the cortex and was found to be approximately doubled in th~ arlimal~
5 treated with (Tl)-4 ~ninohex-S-ynoic acidJ During the first week o~ treatlnent, the animals lost body weight an~
lost hair on their backs. These effects appeared to disappear during the second week, however.
At dosages of 100 and 200 mg/kg, a~ministered i.p., 10 ~R)-4-aminohex-5~ynoic acid was shown to protect mice against convulsions and death, induced by mercapto-propion.ic acid~ administered at a dose of 53 mg/kg, i.p., 6 hours after injection of ~R)-4-aminohex--5-ynoic acid.
HoweverD no protection against running ~its was af~orded.
At a single ~ose of 400 mg/kg, i.p., in mice, (R~-4-aminohe~-5-ynoic acid produced sedat~on within 30 minutes~ but 24 hours later the animals were dead.
(S3-5-~xo-2-pyrrolidine-aceton~trile ~ Compound (1) 3 and its preparat~on from L-glutamic acid ~ia (S)-20 5-tosyloxymethyl-2-pyrrolldinone by the reactlon sequence ~hown in CHART 2 (Steps E, F, G9 H~ and I) are described by Hardeg~er and Ott~ HelvO Chim. Acta, 38, 318 tl955).
The reduction of ethyl-(S~-pyroglutamate with sodium borohydride in ethanol i~ described by Sai~ et al., - lB -Chem~ Pharm. Bull., 28, 1449 tl98C))~ The reduction ~r ___ _ ethyl- ~ S ~ -pyroglutamate wi th 1~ thium borohydrld~ ia described by Bruckner et al , Acta Chim. Htln~ , 21, 105, 116 (1~5g). The preparatlon Or ethyl (S3-pyro~lutamat~
5 from diethyl L-glut~ma~e is descrlbed by F'ischer and Boehner, Chern Ber., 44, 1333 ~1911) and Abderhalden and Wield, Hopp -Seiler's Z ~. Physiol. Chem., 74, 459 tl911).
In its composition-of-matter aspects, the present 10 invention comprehends N,N-dimethyl-2-~ 5l-oxo-2'-pyrrolidine ]ethylamine or the N oxide thereof, or an acid addition ~alt thereof.
The following Example~ will lllustrate processe~ for carrying out the i~ventionO As employed in the Examples~
15 "T~F" means tetrahydrofuran and "DM~ means dimethylformamide. Drying of organic extracts was accomplished using anhydrous sodium sulfate.
Example l Ethyl L-pyroglutamate Thionyl chloride (217 ml) is slowly added to a stirred suspe~sion o~ L-glutamic acld (417 g) in dry ethanol (1 L), and the mlxture is refluxed for 5 hour~.
Ethanol is removed under ~accum to give a res~due, which is dissolved in water (500 ml). The water solution is 25 ma~e alkaline with saturated sodium carbonate solution 2~-31~13 ~Z~

and extraeted wlth chloro~orm (4 x ~00 ml~. The chlorororm extract is dried (Na~S0~3 and evaporatcd ~o give erude product (178 g~. This rnatcrial i~ heclte~
~160C) w~der vacuum (10 r~ Hg) ~or 3 hours. S~bsc~uen-t 5 distlllation gives pure ethyl L-pyro~lutam~tc (126.6 g;
b.p~ 126~C/0.07 r~ H~; C a ~D -- ~2.15~0.01 (HzO, c-17.~.
Example 2 -( 5 ~ -5-Hydroxymethyl=2-pyrrol i dinone Under an atmosphere of nitrogen, ethyl L-pyroglutamate (31.4 g), obtained as in Example 1, dissolved in THF (100 ml~, ls added slowly to a stirred suspension o~ lithium borohydride ~8 g~ in dry THF (260 ml3. During the addition, the temperature is kept below 15 40DC. The mi~ture is then stirred at room temperature ~or 48 hours. Water ~50 ml~ ~nd THF (150 ml) is added7 and the resulting mixture is stirred overnight. Filtration (meth~nol washing) and evaporation of solvent gives a residue which is digested with methanol (100 ml3r ~he 20 mixture is f~ltered (chloroform washing, lnO ml~, evaporated and dissolved in chloro~orm again. Filtratio~
and evaporation give the title compound as ~n oil: 24.2 g.

~ M-31413 - 20 ~
Example 3 (S)-5- r ~ e_lanesul_onylox~ ~-meth~1_ 2-pyrrol.ldinor Crude (S~-5~hydroxymet.hyl~2~pyrrolidir,orle (13 ~
5 obtalned as in Example 2, dissol~ed in dry pyrid:Ln~ ~lZ0 ml), and cooled with ice, ls trcated with mesylchloride (10 ml)> keeping the temperature below 5C. The mixture is allowed ~o warm to room temperature and is stirred for 1 more hour. ~ater (2 ml) is added, and the mixture is 10 stirred for 10 more minutes. The solvent is removed under vacuum9 and the residue obtained is d~gested with dichloromethaneO The mixture is filtered tmethYlene chlor~de - washing) and solvent is remove~ by e~aporation to give a residue. The residue is dissolved in water (100 15 ml) and the re~ulting solution is treated with a cation exchange resin (H~-form, 2 g) and an an~on exchanger (OH~
-form, 2 g~. Filtration and evaporation g~ve an oil which is d~ssolved ln chloro~orm. After removal o~ insoluble material~ drylng and evapvration gi~e crude title 20 compound, 16.8 g. Thls materlal '1~; recrystallized from cold methanol to yield 12.12 g.
Example 4 (S~-5-Oxo-2-pyrrolidine-acetonitrlle A mixture Or (S)-5-[ methanesulfonyloxy ]methyl-2-Z5 pyrrolidinone (19.3 gj, obta~ned as ln Exam~le 3, sodium ~6~3 2~-31~13 cyanide (7.3 ~, sodlum iodide (50 tng~ and dry DMF (100 ml) i~ stlrred and heated at 90~C for 3 hour~. S~irrin~
i5 contlnued at room temperature overni~ht. Salt~ ~re then removed by f~ltration (dichloromethane w,a~3hirl~). The 5 residue obtalned on evaporation is dissolved ln- -dichloromethane ~50 ml)~ insoluble ~aterial is ~iltered off~ and the rlltrate ~s evapora~ed again. Ethyl acetate (5 ml) is added. Crude ~itle compound (11.4 ~) crystallizes upon standing overnight (5C~.
10 Recrystallization from ethyl acetate/diethyl ether ~ives the pure title compound (9.2 g).
Example 5 (S)-NgN-Dimethyl-2~ r 5'-oxo-2'-pyrrolidine ]-ethylamine To a solution o~ ~S)-5-oxo~2-pyrrol~dine-acetonitrile (9.42 g, 80 mmole), obtained as ln Examplc 4, ln ethanol (80 ml)~ a 33% solution o~ dimethylamine in ethanol (28 ml) is added~ and the resulting mixture is hydrogenated overnight (30 p~ ) ln the presence of 20 palladium-on-barium sul~ate (5%, 12 g)~ Dlstillation gives the title compound ~8.63 g3, b.p. ~05-110C /
O . 1 ~ mm ~,~ .

~-31413 ~2~ 3 _ 22 -Example 6 (S~-5-V.lnyl-2 ~ rrolidi~one (S~-N,N-Dimethyl-2-t 5~-oxo-2'-pyrrolldlne ~e~hyl-amine (3~69 g), obtained as 1n E~.~nple 5, dissolved ln 5 water (10 ml), is treated with 30~ hydro~en peroxlde (2.66 g)O After 2 hours, more hydrogen peroxide ~Z.66 8~
is added~ and stirring is continued for 60 hours~ A th~rd portion of 30% hydrogen peroxide ~2.65 g~ is then added, and stirring is continued for another 24 hours to 10 eomplete the oxidatlon (pH neutral~. The excess Or hydrogen perox~de ~s destroyed by stirring (12-24 hours3 wlth a few mg vf catalase; absence of hydrogen perOXide ls tested for with "Mercko~uant" peroxlde test paper, The mixture is filtered and e~aporated to give the crude N-15 oxide (presumably as a hydrate) as an oil (4.7 g). Thiso~l is heated under ~a cuum (0.1 ~n Hg). At 130Cu ~l~e material ss:>lidifies, and at 160C (bath temperature~ the title. compound dist~ls (2.3 g). According to ~S analysi the crude product contains ~ 40% of (S)-N,N-d~met~ 2_ 20 ~ 5'-oxo-2'-pyrrolidlne ~ethylamine.
Example 7 ~S~-4-Amino-5-hexenoic acld Crude (S~-5-vinyl-2-pyrrolidinne (1~97 g)~ ~btained as irl Example 6, i5 heated with 5% aqueous hydrochlorie 25 acid (50 ml) at 95~C for 5 ~loursu After evaporation o~

* Trade Mark ~ z~ 31~13 - 23 ~
solvent, the resultlng re~idu~ is dissolve~ in a Mi~ture Or ethanol (5 ml) ~d isopropanol (lZ rnl). Upon addition of trlethylamine until pH 7-8, the crude tltle compotlrld precipitates (1.0 g). This rnatcrial ~.s dissol~c~d in water 5 (2 ml). Trcatrnent wlth charcoal (90C, 30 m~nuteC;)~ ~nd addition of cthanol (10 ml~ and isopropanol (2 ml) give pure title compound which crystaLlizes on standlng at 5~C
overn~ght. Addition o~ more isopropanol gives a second erop; total: 450 mg; C a ~D=12.4~0.6 (H20, c=0.515), 6C
10 ~opt. active column -~ MS): optical purity at best ~9% (no R-lsomer detec~able).
Example 8 ~S)-5-Vinyl-2-pyrrolidinone The oxidation o~ (S)-~,N-dimethyl-2-E 5'-oxo-2'-15 pyrrolidine ]ethylamine is repeated according to the procedure of Example 6. Excess of hydrogen peroxide is destroyed with platinium black. The mixture is filtered and the fil`trate is extracted with chloroform~ The aqueous phase is eYaporated t~ give a residue. Thi~ i8 20 dissolved ln a ~ew ml o~ ethanol. E~aporation o~ solvent ,~ives the N-oxlde ~presumably as the hydrate~ a~ a white solid. Recrystallization ~rom ethanol giveE 7.1 g of ImatPrial (starting from 8.63 g Or the amine starting material). On dry dlstillation~ (S~-5-vinyl-2-2S pyrrolid~none distils at 150C (0,1 mm Hg~ bath 1~6~ M-31~1~

tcmperature, The temperature is raised f~nally to 185~Co Aecordin~ to I~R analysls, the slightly yellow coloure~
d~stillate (4-07 g~ contains about 25 MOIC-~ Or (S)-N,N~

dilnethyl--2-C 5~-oxo-2~-pyrrolidine J e1 hyl~lnin~ . r~e 5 distillate :Is dissolved in ~ ter (~0 ml~ and the resulting solution i5 treated with ~n ion exehange re~in (~Jnberlite R 150; ~-form? until neutral (10 ml of wet resin). Filtr~tion, evaporation, and distillation (b.p.
130C/0~ mm Hg) give (S)-5-vinyl-2 pyrrolidinone as a 10 colourless li~uid ~ 2.486 g, hygroscopic, purity ~ 98%
(GC/MS) 3. The resin i~ collected and treated with 6N H~l ~2 x 50 ml) and washed with water (50 ml3. Evap~ration of solvent gives (S3-N,N-dimethyl-2- r 5 ~ -oxo-2~-pyrrolidine ]ethylamine tas the hydrochloride) RS a solld 1~ (i.47 g)~
Example 9 (S~-5-Tosylox~methyl-2-pyrrolidinone Ethyl ~L~-pyroglutamate (15.7 g), dissolved in water (50 ml) ls added ~lowly at 0C to a solution o~ sodium 20 borohydride ~2~2 g) in water (50 ml?. The mixture ~s allowed to warm up over a one-hour perlod after which i~
i~ ~tlrred at room temperature for 20 minutes~ Acetone (5 ml) i~ added and the stirring i~ continued for 30 mi:nutes. Solvent is evaporated to give a dry residue 25 which ls diss~lved in w~ter (100 ml). The ~olution ~s ~-31413 ~2~62~

- ~5 -then c~ncentrated to a vol~ne Or 40 ml. To ~he concentrated solut.ion are added: caustic soda ~5 ~, tosyl chloride (18.10 ~ in dlchloromethane (100 ml~ ~nd tetra-n--butyl amrnon~tlm hydrof~en sulratc (1.03 g~ The S resulting rlixture .is stlrred ~i~orously for 42 hour~ at room teMperature. The orK~n~c layer is separated~ ~d the aqueous layer is exkracted with dichloromethane (~0 ml) The organic layers are combined and dried. Evaporation o~
solvent gives a residue which is recrystallized from ~0 toluene ~150 ml) to give 13.6 g of pure (S)-5-tosyloxymeth~ 2-pyrrolid~none, ~ a ~D= ~ 7.80+0.04 (c-2. 64, EtOH) .
Example 10 (R)-S-Vlnyl-?-pyrrol~ dinone To a stirred suspension o~ (R)-4-amino-5-hexenolc acid (2.5~ g, 20 mmoles) in methan~l (20 ml), thionyl chloride (1.5 ~l~ i~ added dr~pwise wlth ~ce eooling.
After.rerluxing for 3.5 hours t evaporation of solvent gi-ves an o~l which i~ d~solved in water (-lS ml). Sodium 20 carbonate (4 g~ is added, and the resulting mlxture i~
extracted 3 times with dlchloromethane. Drying and evaporatlon gives the methyl ester as an oll (2~B5 g)~
M~R (CDCl3): ~ 1.35 (2H, ~(NH23~; 1.62-2.03 (2H, m);
2.17-2.58 (2H, m~ 3~ ~1H, q, J=7 Hz);

3.67 (3H, ~); 4.87-6.10 t3~, m).

~ 31413 The oil is heated in toluene ~bath temperature:
120C~ for 40 hours. Distlllation in a Ku~elrohr (0.1 r~n Hg~ 140C) gives the tikle compound as a colorless oil (1.57 g~: ~ a ~ (EtOH, c-4):
5 -54 84-~0 o~ D
~MR (CDCl~ 1.47-2.,53 (4H, m); 4.13 (lH~ broadened q, _.
3-7 H~); 4.93--6.13 (3H, m); 7.53 (lH9 broad s~

Example 11 (R)-5-(1',2'-dibromoethyl)-2-pyrrolidinone . . _ .
To a solution of (R)-5-vinyl-2-pyrrolidinone (1.28 g~ 11.5 mmoles) obtained as in Example 10, ln carbon tetrachloride ~lB ml) is added a solution of bromine ~0.67 ml) in carbon tetrachloride ~5 ml) dropwise 15 with ice cooling and stirring. During this addi~ion, a viscous oil separates. After the addition, stirri.~ is continued for 1 hour at room temperature. The solvent is remoYed under vacuum, and the residue obtained is dissolved in dichloromethane and washed with loX sodium 20 bisul~ite solution until nearly colorlessO The aqueous phase is made basic with (~olid) sodium carbonate ~nd extracted ~wice with dichloromethane. The c~mbined organic phase~ are dried and evaporated to glve an oil which is puri~ied by ~`lash chromatography on silica gel ~ 9~ 31~13 t200 g, ~luent: hexane/ethyl ace~ate/chlorororm/meth~n~l 3:2"2:1; R~ (s~ne solvent): 0.33~. The pure ~itle compound crystallizes on evaporation and i5 Ob~airlC'd ~lS a white solid 1.54 g~, 5 l7MR ~CDCl,~: ~ 1.6-2.75 (4H, rn); 3.5-3.93 anfl 3,93 4.53 (4H~ 2-n); .7.63 (1HJ broad s)~
Ex~nple 12 (R)-5-Ethynyl-2=pyrrolidinone To a suspens~on of potassium-tert-butoxide (3.57 g) 10 in d:ry THF (10 ml)~ cooled at -65C, a solution of (R)-5-(1',2'-dlbromoethyl)-2-pyrrolidinone ~1.44 g, 5.31 mmoles) obtained as in Example 11, in THF (20 ml~ ~8 added slowly, whereby the internal temperature is kept -bekween 60C ~d -65~C. The mixture is allowed to warm lS up to -20C; then it is poured lnto a vigorously stirred ice-cold solution of acetic acid (2.5 g) .ln water (10 ml~ The mixture is diluted with ethe:r (50 ml~ The a~ueous layer is separated~ made basic with sod~m carbonate~ and extracted twlce with dichloromet~ane. The 20 combined vrg~nic phases are dried and evaporated to give an oll ~h~ch still contains acetic acid. It is dissolved in water ~20 ml), and solld sodium carbonate is added until basic. Three extractions with dichloromethane, dry~ng and evaporation give an oil (0.62 g~ which is 25 puri~ied by chromatography on sillca (100 g; eluen~:

- lZ~6~ M-31413 - 2~
hexane]ethyl acetate/chloroform/methanol 3:2:2:1; Rr (same solvent): 0.23~. Pure title compound ls obtalrled a~
a white solid (0.33 g): ~ a ~ (EtOH, c=3.~):
~15.~2-~0.06~
5 NM (CDCl ): ~ 1.92-2.73 (SH, rn); 4.40 (lH, M3, 7.95 (lH~
broad s).
Example 13 (R)-4 Aminohex-5-ynoic acid (R)-5-Ethynyl-2-pyrrolidinone, obtained as in 10 Example 13, is treated with 2N hydrochloric acid at 100C
for 6 hours. Solvent ls removed by evaporation and a crude product is obtained. The crude amino acid product is converted to the methyl ester, N-trirluoroacetyl derivativeg and the derivative is analyzed by &C
15 ("chirval'~)~ which indicated an opt~cal purity of 100~, with no S-enantiomer detectable.

Claims (10)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing M,N-dimethyl-2-[5'-oxo-2'-pyrrolidine]ethylamine, or the N-oxide thereof, which comprises reacting 5-oxo-2-pyrrolidine-acetonitrile with hydrogen and dimethylamine in the presence of a palladium catalyst and, when the N-oxide is required, oxidizing the N,N-dimethyl-2-[5'-oxo-2'-pyrrolidine]ethylamine product of said reaction.

2. A process according to Claim 1 wherein the reaction with hydrogen and dimethylamine is conducted in a (Cl-C6)-alkanol and/or water solvent at a temperature of from 20 to 100°C and in the presence of 1 to 20 atmospheres of hydrogen gas using a palladium-on-barium sulfate catalyst.

3. A process according to Claim l wherein the N,N-dimethyl -2-[5'-oxo-2'-pyrrolidine]ethylamine product is oxidized to the N-oxide thereof.

4. A process according to Claim 3 wherein the oxidation is conducted with hydrogen peroxide in water and/or a (Cl-C6) alkanol solvent.

5. A process according to Claim 1 wherein the 5-oxo-2-pyrrolidine-acetonitrile is in the form of the (S)-enantiomer.

6. The compound, N,N-dimethyl-2-[5'-oxo-2'-pyrrolidine]-ethylamine or the N-oxide thereof, when produced by the process of Claim 1.

7. The compound, N,N-dimethyl-2-[5'-oxo-2'-pyrrolidine]-ethylamine or the N-oxide thereof, when produced by the process of Claim 2.

8. The N-oxide of N,N-dimethyl-2-[5'-oxo-2'-pyrrolidine]-ethylamine when produced by the process of Claim 3.

9. The N-oxide of N,N-dimethyl-2-[5'-oxo-2'-pyrrolidine]-ethylamine when produced by the process of Claim 4.

10. The compound N,N-dimethyl-2-[5'-oxo-2'-pyrrolidine]-ethylamine or the N-oxide thereof, when produced by the process of Claim 5.