Note: Descriptions are shown in the official language in which they were submitted.
~ 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
-- 2 --
~ 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:
M-31413
~Z16~
-- 4 --
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
0 1 2
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~
-- 6 --
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
- M-31413
-- 7 --
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~
-- 8 --
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
-- 10 --
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~ ].
15CHART 2
.
Ho2cc~2cH2~Hco2H2 E
NH2
~5)
2~ _
R2CCH2CH2CHC2R2 _ F
NH~
(6
2~-31 413
i~3~3
11 --
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
- 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
- 14 -
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
31 103
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~
- 17 -
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.,
M-31413
- 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~
-- 19 --
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~
- 24 -
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
- 26 -
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
- 27 -
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.
