CA1244041A - Process for the preparation of cis, endo- octahydrocyclopenta¬b|pyrrole-2-carboxylate - Google Patents
Process for the preparation of cis, endo- octahydrocyclopenta¬b|pyrrole-2-carboxylateInfo
- Publication number
- CA1244041A CA1244041A CA000487583A CA487583A CA1244041A CA 1244041 A CA1244041 A CA 1244041A CA 000487583 A CA000487583 A CA 000487583A CA 487583 A CA487583 A CA 487583A CA 1244041 A CA1244041 A CA 1244041A
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- compound
- substituted
- lower alkyl
- iiia
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Abstract
ABSTRACT
Novel process for the preparation of cis,endo-octahydrocyclopenta [b]pyrrole-2-carboxylate (IIIa) IIIa wherein R6 is hydroxy, lower alkoxy, lower alkenoxy, dilower alkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, aryloxy, aryllower-alkoxy, amino, lower alkylamino, dilower alkylamino, hydroxyamino, aryllower alkylamino, or substituted aryloxy or substituted aryllower alkoxy wherein the substituent is methyl, halo or methoxy, which comprises catalytic reduction of compound II, II
which further may comprise preparing the compound of formula II by the reaction of a halo pyruvate ester (V) V
with benzyliminocyclopentane. Compounds IIIa are useful intermediates for the preparation of certain ACE-inhibitors
Novel process for the preparation of cis,endo-octahydrocyclopenta [b]pyrrole-2-carboxylate (IIIa) IIIa wherein R6 is hydroxy, lower alkoxy, lower alkenoxy, dilower alkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, aryloxy, aryllower-alkoxy, amino, lower alkylamino, dilower alkylamino, hydroxyamino, aryllower alkylamino, or substituted aryloxy or substituted aryllower alkoxy wherein the substituent is methyl, halo or methoxy, which comprises catalytic reduction of compound II, II
which further may comprise preparing the compound of formula II by the reaction of a halo pyruvate ester (V) V
with benzyliminocyclopentane. Compounds IIIa are useful intermediates for the preparation of certain ACE-inhibitors
Description
Inhibitor3 o angioten~in-converting enzymes are useful in the treatment o cardlova~cular di~orders aspecially a~ antihypQrtensivo agents and al~o in the treatment of congostive heart failure and oÇ
glaucoma~ Such ACE-inhibitorY have, or axample, been described in tha published European patent applications No~. 50800 and 79022-Of particula~ interest as ACE-inhibitor~ are compound~ o the general ~ormula (I) Y~
R-~- ~ -NH-~H-~;N -CH _~_R6 ~ ~ ~.* *
and tho pharmaceutically acceptable ~alt.~ thereof, wherein R and R6 are ~he same or different and are hydroxy, lower alkoxy, lower alkanoxy, diloweralkyl-amino lower alkoxy (e.g. dimethylaminoethoxy), acylamino lower alkoxy (e.g. acetylaminoethoxy), acyloxy lower alkoxy (e.g. pivaloyloxyethoxy), aryloxy (e.g. phenoxy), arylloweralkoxy (e.g. benzyloxy), amino, lower akylamino, diloweralkylamino, hydroxy-amino, aryllower alkylamino (e.g. benzylamino), or substituted aryloxy or substituted arylloweralkoxy wherein the substituent is methyl, halo or methoxy;
Rl is hydrogen, alkyl of from 1 to 10 carbon atoms, including branched and cyclic and unsaturated (e.g. allyl) alkyl groups, suhstituted lower alkyl wherein the substituent: is hydroxy, lower alkoxy, aryloxy (e.g. phenoxy), substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, lower alkylamino, diloweralkylamino, acylamino, arylamino, substituted arylamino, guanidino, imi-dazolyl, indolyl, lower alkylthio, arylthio (e.g.
phenylthio), substituted arylthio, carboxy, carbamoyl, lower alkoxycarbonyl, aryl (e.g. phenyl or naphthyl), substituted aryl, aralkyloxy, substituted aralkyloxy, aralkylthio, or substituted aralkylthio, wherein the aryl or heteroaryl portion oE said substituted aryloxy, heteroaryloxy, arylamino, arylthio, axyl, aralkyloxy or aralkylthio groups is substituted with a group .selected from halo, loweralkyl, hydroxy, lower alkoxy, amino, aminomethyl, carboxyl, cyano and sul~amoyl; and R3 is hydrogen, lower alkyl, phenyl lower alkyl, aminome-thylphenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl (e.g. benzoylamino lower alkyl or acetylamino lower alkyl), amino lower alkyl, dimethyl-amino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, or lower alkylthio lower alkyl.
As used herein, acyl includes -C-R12 wherein R12 is lower alkyl, lower alkenyl or aryl.
The lower alkyl or lower alkenyl groups except where noted otherwise are represented by any of the variables including straight and branched chain hydrocarbon radicals from one to six carbon atoms, for example, methylt ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl or vinyl, allyl, butenyl and the like. Cycloalkyl groups include bridged and non-bridged groups.
The aralkyl groups represented by any of the above variables have from one to four carbon atoms in the alkyl portion thereof and include for example, benzyl, p-methoxybenzyl and the like. Halo means chloro, bromo, iodo or fluoro. Aryl, where it appears in any of the radicals, except where noted, represents phenyl or naphthyl. Heteroaryl groups where~ they appear include for example pyridyl, thienyl, furyl, indolyl, benzothienyl, imidazolyl and thiazolyl. The Rl and R3 substituted lower alkyl moieties are çxemplified by groups such as ~ ~LCH2_ ~ ~CH2 ~H2--H H
HC-CH2-' HS-CH2-~ H2N-(cH2)4-, CH3~S-(CH2)2_, NH
glaucoma~ Such ACE-inhibitorY have, or axample, been described in tha published European patent applications No~. 50800 and 79022-Of particula~ interest as ACE-inhibitor~ are compound~ o the general ~ormula (I) Y~
R-~- ~ -NH-~H-~;N -CH _~_R6 ~ ~ ~.* *
and tho pharmaceutically acceptable ~alt.~ thereof, wherein R and R6 are ~he same or different and are hydroxy, lower alkoxy, lower alkanoxy, diloweralkyl-amino lower alkoxy (e.g. dimethylaminoethoxy), acylamino lower alkoxy (e.g. acetylaminoethoxy), acyloxy lower alkoxy (e.g. pivaloyloxyethoxy), aryloxy (e.g. phenoxy), arylloweralkoxy (e.g. benzyloxy), amino, lower akylamino, diloweralkylamino, hydroxy-amino, aryllower alkylamino (e.g. benzylamino), or substituted aryloxy or substituted arylloweralkoxy wherein the substituent is methyl, halo or methoxy;
Rl is hydrogen, alkyl of from 1 to 10 carbon atoms, including branched and cyclic and unsaturated (e.g. allyl) alkyl groups, suhstituted lower alkyl wherein the substituent: is hydroxy, lower alkoxy, aryloxy (e.g. phenoxy), substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, lower alkylamino, diloweralkylamino, acylamino, arylamino, substituted arylamino, guanidino, imi-dazolyl, indolyl, lower alkylthio, arylthio (e.g.
phenylthio), substituted arylthio, carboxy, carbamoyl, lower alkoxycarbonyl, aryl (e.g. phenyl or naphthyl), substituted aryl, aralkyloxy, substituted aralkyloxy, aralkylthio, or substituted aralkylthio, wherein the aryl or heteroaryl portion oE said substituted aryloxy, heteroaryloxy, arylamino, arylthio, axyl, aralkyloxy or aralkylthio groups is substituted with a group .selected from halo, loweralkyl, hydroxy, lower alkoxy, amino, aminomethyl, carboxyl, cyano and sul~amoyl; and R3 is hydrogen, lower alkyl, phenyl lower alkyl, aminome-thylphenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl (e.g. benzoylamino lower alkyl or acetylamino lower alkyl), amino lower alkyl, dimethyl-amino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, or lower alkylthio lower alkyl.
As used herein, acyl includes -C-R12 wherein R12 is lower alkyl, lower alkenyl or aryl.
The lower alkyl or lower alkenyl groups except where noted otherwise are represented by any of the variables including straight and branched chain hydrocarbon radicals from one to six carbon atoms, for example, methylt ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl or vinyl, allyl, butenyl and the like. Cycloalkyl groups include bridged and non-bridged groups.
The aralkyl groups represented by any of the above variables have from one to four carbon atoms in the alkyl portion thereof and include for example, benzyl, p-methoxybenzyl and the like. Halo means chloro, bromo, iodo or fluoro. Aryl, where it appears in any of the radicals, except where noted, represents phenyl or naphthyl. Heteroaryl groups where~ they appear include for example pyridyl, thienyl, furyl, indolyl, benzothienyl, imidazolyl and thiazolyl. The Rl and R3 substituted lower alkyl moieties are çxemplified by groups such as ~ ~LCH2_ ~ ~CH2 ~H2--H H
HC-CH2-' HS-CH2-~ H2N-(cH2)4-, CH3~S-(CH2)2_, NH
2 (CH2)3 , H2N C-NH-(CH2)3- and the like-Preferred compounds of formula I are those in which R is hydroxy or lower alkoxy, Rl is lower alkyl or sub3tituted lower alkyl wherein the substituent is aryl, R3 is lower alkyl or amino-loweralkyl and R6 is hydroxy.
The aforementioned compounds of the formula I, as defined above, include all possible stereo-isomers. Preferred stereoisomers are the cls,endo-octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acids, wherein preferably the absolute configuration at the carbon atoms marked by a double asterisk in the above formula I is most similar to that of natural L-amino acids, which usually are assigned the S-configuration. Particularly preferred compounds are l-[N-(l(S)-carboxy-3-phenylpropyl)-(S)-alanyl]-cis,endo-octahydrocyclopenta[b]-pyrrole-2(S)-carboxylic acid, l-[N-(l(S)-carboethoxy-3-phenyl-propyl)-(S)-alanyl]-cis,endo-l octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acid, l~N ~-(l(S)-carboethoxy-3-phenylpropyl)-(S)-lysyl]-cis,endo-octahydrocyclopenta~bJpyrrole-2(S)-carboxylic acid, l-~N~-(l(S)-carboxy-3-phenylpropyl)-(S)-lysyl]-cis,endo-octahydrocyclopenta~b]pyrrole-2(S)-carboxylic acid, l-~N-(l(S)-carboxybutyl)-(S)-alanyl] cls,endo-octahydrocyclopen-ta~b]pyrrole-2(S)-carboxylic acid, l-~N-(l(S)-carboethoxybutyl)-(S)-alanyl]-cls,endo octahydrocyc:lopenta~b]pyrrole-2(S)-carboxylic acid, 1-~N ~ -(l(S)-carboethoxybutyl)-(S)-lysyl]-cls,endo-octahydrocyclopenta~b~pyrrole-2(S)-carboxylic acid, and 1-~N ~ (l(S)-carboxybutyl)-(S)-lysyl]-cls,endo-octahydrocyclopenta~b]pyrrole-2(S)-carboxylic acid or their hydrochloride salts. A most preferred compound is l-~N-(l(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-cls,endo-octahydrocyclopenta~b]pyrrole-2-(S)-carboxylic acid and its hydrochloride salt.
These compounds can be prepared by known methods such as described in the above mentioned European published patent applications Nos. 50800 and 79022.
One of the starting materials for the preparation of compounds of formula I is oc-tahydro-cyclopenta~b]pyrrole-2-carboxylate, III, .~
~S$
wherein R6 is a~ ds~ined abov~.
Compound~ o for~ul~ conYl~t o~ eiqht st2reoisomer~ co~po~d of ~our race~lc pa~r~ the two Ci9 epimer~, IIIa and IlIb, and the two tran~ epimsrs, IIIc and rIId:
~t:oR~ ~ ~COR6 (~) IIIa (~ IIIb (~ IIlc (~ IISd A~ u~ed herQin, the fo~mulae III~, IIIb, IIIc and IIId are meant to co~pri~o the rel~vant racQmic pair of optical isomer~.
The compound~ of formula III can be prapared by known mathods, suoh a~ di~cloqed in ths publicationq mentioned above, followod, if de~ired, by isolation of the racemic pairs of isomers or their individual component enantiomers according to resolution methods well described in the art.
The present invention provides a novel process for the preparation of the compounds of the - 6 ~
~en~ral fon~ula IIIJ9 Th~ proce~9 compri~e~ c~talytic rcduc~lon o~ co~pound I~
N ~
C~2C~j~S
wharein R6 i5 a defined above, followed, if desired by the resolution of the racemic mixture to obtain the individual enantiomer.
Compound II can be prepared by the reaction o a halopyruvat~ e~ter (V) Hal-CH2-~ R6 wherein R6 i3 as deflned above and Hal stands for halogen, with benzylimlnocyclopentane.
Thi3 procedure can be exempli~ied by the followlng reaction schemes OD~N-CN2-C6~S I ar CH2 ~ ~ R
~V ~Ja, iC2H5)3~
~ co~6 ~
I P~/C IIIa C~2C6~5 t~
~7-The ~roc3~ for preparing tho novel compound~
~ benzyl~ 5,6-~otrahydrocyclopent~n0[b]pyrrolo-2-carboxylic aGid or it o~ters) pr~ferably u~e~ a lower alkyl ester of bromo pyruvate (a.g. R6 i~ othoxy, methoxy or t~butoxy)O Pref~rably, equimolar amounts of reac~ant~ are used. The r~actio~ i~ carried out in an in~rt ~olvent such a~, for exa~ple, an alcohol (ocg.
ethanol), acetoni~r~le or dim~thylform~ide in the pre~ence of a b~e ~uch a~, for exa~pl~, triothyl-amine. The reactlon may bo carried out at from 0-100C
for 2-~ hour~, but i~ preferably carried out at low temperature~ (e.g. 0-5C) for approximately 2 hours, then at re~lux (temperature depends on ~olvent) for 2 hours.
The catalytic reduction o~ compound II to saturate the ring and remove the benzyl g~oup is carried out in a solvent such a~ an alcohol (e.g.
ethanol) in the presence of hydrogen gas and a cataly~t such as Pd(OH)2 on carbon, Pd on carbon or other appropriate cataly~t~. The resultant product may be i~olated by me~hods woll known to those skilled in the art, e.g. by treAting wlth an acid such as HCl to prepare the salt, followad by removal of the salt ~e.g.
by basifying with 30dium hydroxid~) to obtain the compound of formula IIIa, followed, if desired by the isolation of the individual enantiomers.
In the above reactions, the group R6 being other than hydrogen (especially aryllower alkyl) can be hydrogenolyzed to some extent. Consequently, an addi-tional esterification step may be required to obtain the desired compound.
The above described process is stereospecific so that compounds IIIa (cis,endo-form)are obtained directly. These compounds are useful in the -8~
preparation of the preferred compounds of formula I
(listed above) which are also the cis,endo-isomers.
This i9 a great advantage over the known method for preparing compounds of formula (III) which are not stereospecific so that additional process steps have to be carried out to isolate the desired isomer of the intermediate (III) or of the end product (I).
Compounds IIIa as obtained by this process are racemic mixtures. The individual enantiomers can be obtained by conventional resolution methods well described in the art such as fractional crystallization of appropriate diastereomeric salts, for example the fractional crystallization of compounds IIIa wherein R
is benzyloxy or its benzyloxycarbonyl-L-phenylalanine salt.
The compounds of formulae IIIa (cis,endo-forrn) can be converted to the correspondin~
compounds having the cis-exo~form (IIIb)~ Such epimerizations are most conveniently carried out on the free base ester forms of the.se compounds, in the absence or presence of additional basic catalysts such as potassium t-butoxide, triethylamine and the like.
The following examples illustrate the process of this invention, the preparation and use of the compounds of the present invention. The diastereoisomers prepared as set forth below may be isolated by column chromatography or by fractional crystallization.
.9_ liX~PLE 1 CARI!IOXYl.ATE
Add dro~wi~ 3 . 9 gm o ethyl bromopyruvata in 50 ml of ethanol to a fla~k COnt21iniR9 3-46 910 oi~
benzyliminocyclopflntanQ and 2.09 o~ triethylaroin~ in 50 ml of ethanol at 0C~ stir ~or 2 hourY, then heat to re1ux for 2 hour~. Concentrate th~ reaction mixture and partltion betwaen lN HCl and ~thor. Dry the ether axtract over magne~ium ~ulfate, filtor, concen~rate under high vacuum to obtain a brown oil and diqtlll in a kugelrohr at 190-210/0.1 mm to bbtain the title compound of Part A a~ a yellow oil.
B. Ethyl Ci~,Endo-octahydrocyclopen~a[ble~rrole-2 CarboxYlate H~,cdrochiorideO
Introduce hydrogen ga~ to a mlxture oF 2O3 gm o~ the pyrrole compound produced in part A ~-of this Example and 1.5 gm o 20~ Pd(OH)2/C in 200 ml o~ ethanol, and ~tir the reaction mixture. Ater 24 hours add an additional 0.8 gm of the palladium catalyst. After 600 ml o~ hydrogen gas is absorbed, filter the reaction mixture and concentrate to obtain a liquid and a solid. Take up thQ liquid in ether and filtsr. Treat the filtrate with 2.86N HCl/e~her to obtain an oil which ~olidifies. Filter off the ~olid to obtain the hydrochlorid~ salt of the title compound of Part B as a beige solid. m.p~ 163-7C.
~ecrystallization from CH2C12 and hexano raises the melting point to 171-2C.
c~
Acid.
Stir a ~ixture o2 10.7 ~ o~ ~thyl ci~, ndo-octahydrocyclop~n~2[b]pyrrole-2-carboxylat~
hydrochlorids (fro~ Part ~ abov3) and 175 ml of lN
sodium hydroxide at room tem~era~ur~ for 20 hours and then concentrat~ in vw uo. Place tha rQ~idue on a _ __ silica gel (1000 ~, 69-200 m~sh~ colu~n and ~lute with chlorofor~:isopropanol:7~ ammonium hydroxid~ lsl~l (organic layer) to give cl3,endo-oct~hydrocyclopanta-[b]pyrrole 2-carboxyl~c acld, as a white ~olid, m.p.
220~222C: TLC: Rf 0.12 ~0.25 mm silicaJ ~
CHC13:isopropanol:7~ NH4OH~ low~r pha~e): MS: 156, 155 ~M+), 126 ~M-HCO), 111 (M-CO2), 110 (M-CO2H; 100%), 93 [M-H(CH2)3]~ 82 (M-CH2~CHCO2H), ~0 (M~
H2,CH2~CHCO2H), 68 lM-CO2H, (CH2)3], 67 lM-I
HC02H,(CH2)3] .
MR (400 MHz-D20)~ ~ 4.39 (lH doublet of doublet~
J~llHz,8Hz); 4.20 (lH multiplet);
The aforementioned compounds of the formula I, as defined above, include all possible stereo-isomers. Preferred stereoisomers are the cls,endo-octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acids, wherein preferably the absolute configuration at the carbon atoms marked by a double asterisk in the above formula I is most similar to that of natural L-amino acids, which usually are assigned the S-configuration. Particularly preferred compounds are l-[N-(l(S)-carboxy-3-phenylpropyl)-(S)-alanyl]-cis,endo-octahydrocyclopenta[b]-pyrrole-2(S)-carboxylic acid, l-[N-(l(S)-carboethoxy-3-phenyl-propyl)-(S)-alanyl]-cis,endo-l octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acid, l~N ~-(l(S)-carboethoxy-3-phenylpropyl)-(S)-lysyl]-cis,endo-octahydrocyclopenta~bJpyrrole-2(S)-carboxylic acid, l-~N~-(l(S)-carboxy-3-phenylpropyl)-(S)-lysyl]-cis,endo-octahydrocyclopenta~b]pyrrole-2(S)-carboxylic acid, l-~N-(l(S)-carboxybutyl)-(S)-alanyl] cls,endo-octahydrocyclopen-ta~b]pyrrole-2(S)-carboxylic acid, l-~N-(l(S)-carboethoxybutyl)-(S)-alanyl]-cls,endo octahydrocyc:lopenta~b]pyrrole-2(S)-carboxylic acid, 1-~N ~ -(l(S)-carboethoxybutyl)-(S)-lysyl]-cls,endo-octahydrocyclopenta~b~pyrrole-2(S)-carboxylic acid, and 1-~N ~ (l(S)-carboxybutyl)-(S)-lysyl]-cls,endo-octahydrocyclopenta~b]pyrrole-2(S)-carboxylic acid or their hydrochloride salts. A most preferred compound is l-~N-(l(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-cls,endo-octahydrocyclopenta~b]pyrrole-2-(S)-carboxylic acid and its hydrochloride salt.
These compounds can be prepared by known methods such as described in the above mentioned European published patent applications Nos. 50800 and 79022.
One of the starting materials for the preparation of compounds of formula I is oc-tahydro-cyclopenta~b]pyrrole-2-carboxylate, III, .~
~S$
wherein R6 is a~ ds~ined abov~.
Compound~ o for~ul~ conYl~t o~ eiqht st2reoisomer~ co~po~d of ~our race~lc pa~r~ the two Ci9 epimer~, IIIa and IlIb, and the two tran~ epimsrs, IIIc and rIId:
~t:oR~ ~ ~COR6 (~) IIIa (~ IIIb (~ IIlc (~ IISd A~ u~ed herQin, the fo~mulae III~, IIIb, IIIc and IIId are meant to co~pri~o the rel~vant racQmic pair of optical isomer~.
The compound~ of formula III can be prapared by known mathods, suoh a~ di~cloqed in ths publicationq mentioned above, followod, if de~ired, by isolation of the racemic pairs of isomers or their individual component enantiomers according to resolution methods well described in the art.
The present invention provides a novel process for the preparation of the compounds of the - 6 ~
~en~ral fon~ula IIIJ9 Th~ proce~9 compri~e~ c~talytic rcduc~lon o~ co~pound I~
N ~
C~2C~j~S
wharein R6 i5 a defined above, followed, if desired by the resolution of the racemic mixture to obtain the individual enantiomer.
Compound II can be prepared by the reaction o a halopyruvat~ e~ter (V) Hal-CH2-~ R6 wherein R6 i3 as deflned above and Hal stands for halogen, with benzylimlnocyclopentane.
Thi3 procedure can be exempli~ied by the followlng reaction schemes OD~N-CN2-C6~S I ar CH2 ~ ~ R
~V ~Ja, iC2H5)3~
~ co~6 ~
I P~/C IIIa C~2C6~5 t~
~7-The ~roc3~ for preparing tho novel compound~
~ benzyl~ 5,6-~otrahydrocyclopent~n0[b]pyrrolo-2-carboxylic aGid or it o~ters) pr~ferably u~e~ a lower alkyl ester of bromo pyruvate (a.g. R6 i~ othoxy, methoxy or t~butoxy)O Pref~rably, equimolar amounts of reac~ant~ are used. The r~actio~ i~ carried out in an in~rt ~olvent such a~, for exa~ple, an alcohol (ocg.
ethanol), acetoni~r~le or dim~thylform~ide in the pre~ence of a b~e ~uch a~, for exa~pl~, triothyl-amine. The reactlon may bo carried out at from 0-100C
for 2-~ hour~, but i~ preferably carried out at low temperature~ (e.g. 0-5C) for approximately 2 hours, then at re~lux (temperature depends on ~olvent) for 2 hours.
The catalytic reduction o~ compound II to saturate the ring and remove the benzyl g~oup is carried out in a solvent such a~ an alcohol (e.g.
ethanol) in the presence of hydrogen gas and a cataly~t such as Pd(OH)2 on carbon, Pd on carbon or other appropriate cataly~t~. The resultant product may be i~olated by me~hods woll known to those skilled in the art, e.g. by treAting wlth an acid such as HCl to prepare the salt, followad by removal of the salt ~e.g.
by basifying with 30dium hydroxid~) to obtain the compound of formula IIIa, followed, if desired by the isolation of the individual enantiomers.
In the above reactions, the group R6 being other than hydrogen (especially aryllower alkyl) can be hydrogenolyzed to some extent. Consequently, an addi-tional esterification step may be required to obtain the desired compound.
The above described process is stereospecific so that compounds IIIa (cis,endo-form)are obtained directly. These compounds are useful in the -8~
preparation of the preferred compounds of formula I
(listed above) which are also the cis,endo-isomers.
This i9 a great advantage over the known method for preparing compounds of formula (III) which are not stereospecific so that additional process steps have to be carried out to isolate the desired isomer of the intermediate (III) or of the end product (I).
Compounds IIIa as obtained by this process are racemic mixtures. The individual enantiomers can be obtained by conventional resolution methods well described in the art such as fractional crystallization of appropriate diastereomeric salts, for example the fractional crystallization of compounds IIIa wherein R
is benzyloxy or its benzyloxycarbonyl-L-phenylalanine salt.
The compounds of formulae IIIa (cis,endo-forrn) can be converted to the correspondin~
compounds having the cis-exo~form (IIIb)~ Such epimerizations are most conveniently carried out on the free base ester forms of the.se compounds, in the absence or presence of additional basic catalysts such as potassium t-butoxide, triethylamine and the like.
The following examples illustrate the process of this invention, the preparation and use of the compounds of the present invention. The diastereoisomers prepared as set forth below may be isolated by column chromatography or by fractional crystallization.
.9_ liX~PLE 1 CARI!IOXYl.ATE
Add dro~wi~ 3 . 9 gm o ethyl bromopyruvata in 50 ml of ethanol to a fla~k COnt21iniR9 3-46 910 oi~
benzyliminocyclopflntanQ and 2.09 o~ triethylaroin~ in 50 ml of ethanol at 0C~ stir ~or 2 hourY, then heat to re1ux for 2 hour~. Concentrate th~ reaction mixture and partltion betwaen lN HCl and ~thor. Dry the ether axtract over magne~ium ~ulfate, filtor, concen~rate under high vacuum to obtain a brown oil and diqtlll in a kugelrohr at 190-210/0.1 mm to bbtain the title compound of Part A a~ a yellow oil.
B. Ethyl Ci~,Endo-octahydrocyclopen~a[ble~rrole-2 CarboxYlate H~,cdrochiorideO
Introduce hydrogen ga~ to a mlxture oF 2O3 gm o~ the pyrrole compound produced in part A ~-of this Example and 1.5 gm o 20~ Pd(OH)2/C in 200 ml o~ ethanol, and ~tir the reaction mixture. Ater 24 hours add an additional 0.8 gm of the palladium catalyst. After 600 ml o~ hydrogen gas is absorbed, filter the reaction mixture and concentrate to obtain a liquid and a solid. Take up thQ liquid in ether and filtsr. Treat the filtrate with 2.86N HCl/e~her to obtain an oil which ~olidifies. Filter off the ~olid to obtain the hydrochlorid~ salt of the title compound of Part B as a beige solid. m.p~ 163-7C.
~ecrystallization from CH2C12 and hexano raises the melting point to 171-2C.
c~
Acid.
Stir a ~ixture o2 10.7 ~ o~ ~thyl ci~, ndo-octahydrocyclop~n~2[b]pyrrole-2-carboxylat~
hydrochlorids (fro~ Part ~ abov3) and 175 ml of lN
sodium hydroxide at room tem~era~ur~ for 20 hours and then concentrat~ in vw uo. Place tha rQ~idue on a _ __ silica gel (1000 ~, 69-200 m~sh~ colu~n and ~lute with chlorofor~:isopropanol:7~ ammonium hydroxid~ lsl~l (organic layer) to give cl3,endo-oct~hydrocyclopanta-[b]pyrrole 2-carboxyl~c acld, as a white ~olid, m.p.
220~222C: TLC: Rf 0.12 ~0.25 mm silicaJ ~
CHC13:isopropanol:7~ NH4OH~ low~r pha~e): MS: 156, 155 ~M+), 126 ~M-HCO), 111 (M-CO2), 110 (M-CO2H; 100%), 93 [M-H(CH2)3]~ 82 (M-CH2~CHCO2H), ~0 (M~
H2,CH2~CHCO2H), 68 lM-CO2H, (CH2)3], 67 lM-I
HC02H,(CH2)3] .
MR (400 MHz-D20)~ ~ 4.39 (lH doublet of doublet~
J~llHz,8Hz); 4.20 (lH multiplet);
3.00 (lH multiplet); 2.66 ~lH
multiplet); 2.03-1.18 t6H
multiplet); 1.S7 (lH multiplet).
EXUli'LE Z
1- [N- ( 1 ( R, S ~CAR90ETHOXY-3-PHENYLPROPYI. ) - ( S ) -ALANYL]-CIS,E_DO-:)CTAHYDROCYCLOPENTA[b¦ PYRROLE-2(S)-CAI~OIIYLIC AC~D
A. To a solution of 10.0 9 of ethyl-cis,endo-octahydrocyclopenta [bl pyrrole-2-carboxylate in 400 ml o ethyl acetate add 17.0 g of N-benzyloxycarbonyl ~S)-alanine, N-hydroxy~uccinimide ester. Stir the reaction mixture at room temperatura for 20 hours and concen-t ~
trat~ it in vacuoO Placo tho re~du~ on ~ colu~n ofsillc~ g~l (3000 9, 60-200 ~h) and elu ~ with chlorofor~:ethyl acetata ln:l to obtain l-[N-benzyloxy-c~r~onyl-~S ) -alanyll -ci~,sndo-oetahydrocyclop~nta lb] -pyrrole-2-carboxylic acid, ethyl e3~er, a colorless oil [~1D26-3~.6 (C ~ 0.5, ethanol).
~. To a ~olu~ion of 3.22 9 of l-lN-b~nzyloxy-carbonyl-(S)-alanyl]-c~,endo-octahydrocyclo~enta-[b]pyrrole-2-carboxylic acid, ethyl ester in 150 ~1 of methanol, add 20 ml o~ 205 N sodium hydroxide and stir the mixturs at room temparature for lB hour~.
Concentrate the mixturo under nitrogen, dilute the residue with ice-water and then make the mixtura acidic with concentrated hydrochloric acid. Extract tho aqueous ~olution with ethyl acetate and dry the organic phase over magnesium sulfate. Concentrate the organic pha~e and place it on a column of ~ilica gel (500 9., 60-200 mesh). Elute with chloroform:glacial acstic acid 9:1 and i~olate l-lN-benzyloxycarbonyl-(S)-alanyl]-cis,sndo-octahydrocyclo-penta[b]pyrrole-2(S)-carboxylic acid, as a colorle~ oil, [al D26-26 .4 tC =
0.5, ethanol).
C. Dissolve 1.70 g of l-[N-~enzyloxycarbonyl-(S)-alanyl]-ci~,endo-octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acid in 100 ml of methanol. Add 0.40 9 10~ palladium-on-charcoal and hydrogenate the mixture at atmospheric pressure. ~ilter the mixture and concentrate in vacuo to obta in l-[(S)-alanyl]-cis,endo-oc tahydro-cyc lopenta ~b ] pyrrole~2 t S ) -carboxyl ic ac id .
D. Dissolve l-[(S)-alanyl]-cis,endo-octahydro-cyclopentalblpyrrole-2ts)-carboxylic acid in 100 ml o~
ab~olute m~thanol. Add 1.10 g 2-oxo-~-ph~nylbutyric acld, ethyl ~t~r ~nd 20 ml of 3 Ang~trom ~olecular qlevo pellet~ F and ~tlr th~ re~ulting ~ixture at roo~
te~perature for ei~hteon hour Filt~r th~ re~otion mixture and tr~at the filtrate with 0.68 g sodium cyanoborohydrid0 at roo~ tsmperatur~ for two hour~.
Concentrate the mixture under nitrogen ~nd dilut3 the oil with dilute hydrochloric acid and ~tir at room temperature for one hour. Ab~orb th~ aqu~ou~ solution on 200 ml of a XAD-2 (Xohm ~ Haa~ Co. r~in). El~t~
the re in with 2000 ml of wat~r and then with 2000 ml of methanol. Concentr~te th~ m~thanol ~olution and place the residuo on a column of silica y~l ~400 9, 60-200 me~h) and elute with chlorcform~isopropanol:73 ammonium hydroxida ~lsl~ organic layer) to give 1-[N~ R,S)-carbosthoxy-3-phenylpropyl)-~S)-alanyl]-ci~,endo-octahydrocyclopentalb]pyrrole-2(S)-carboxylic acid, a~ a colorle9~ oil, 1al -5.8 (C~10.6, ethAnol).
l-tN-~1~S)-CAR~OETHOXY-3-PHENYLPROPYL)-~S)-ALANYL]-CIS,ENDO-OCTAHYDROCYCLOPENTA~b]PY~ROL~-2tS)-CARBOXYLIC ACID AND THE HYDRO~HLORID~ SALT THEREOF_ Method I
A. Ci~ ,endo-Oetah~roeyeloE~nta ~b] pYrrole-2-Carboxylie Aeid Hydroehloride Method I Add a 20~ HCl in dioxane ~olution ( 100 ml) to 5 9. of eis,endo~
oetahydrocyclop~nta [b~ pyrrole-2-earboxylic acid. Stir the resulting mixture at room temperature for 30 min.
and then concentrate it in vacuo. Wash the white residue with anhydrou~ ether and dry in vacuo to obtain the tltla co~ound o~ Part A a~ a whito ~olld, m.p.
20g-211, M~thod II Dlssolve 0.2 9 o~ ethyl ci~,endo-oc~hydrocyclopent~[bJpyr~ol~-2-Garboxylat~ (freo ba~a or hydrochlorldo from Example 1 in 20 ml of 6N
hydrochloric acid and reflux over~ight. Cool the reaction mixturo, r~move th~ v~la~ile~ under hLgh vacuum and ob~ain th~ titlc product o~ P~rt Ao B. To 5.0 9 of thc product of Part A, add 50 ml of benzyl alcohol and 50 ml of thionyl chlorida and ~tir at room temperature. Concontrate the reaction mixture ln vacuo and recry~tallize the residu~ rom chloroform/ isopropanol to give benzyl Ci3 ,ando-octahydrocyclopenta[bJDyrrole-2-carboXylate hydrochlorida, m.p. 17S.
C. To 5.5 9 o~ the product of Part ~, add 2.6 g of l-hydroxybenzotria~ole, 5.4 9 of N[l~S)-carboethoxy-3-phenylpropyll-(S)-alanine and 4.0 9 o~ dicyclohexyl-carbodiimide ln 80 ml of dimethyl formamide. Stir the raaction mixtur~ at room temperature ~or 18 hour~.
Filter the reaction mixture, and add ethyl acetata to the filtrate. Extract the ethyl acetate solution (3 X
200 ml) with 5~ aqueou~ codium bicarbonate.
Concentrate the dried ~MqSO4) ethyl acetate solution in vacuo. Chromatograph the residue on a silica gel column (400 g, 60-200 mssh) and eluta with ethyl ace~ate/petroleu~ ether (30-60) 2~ olata, a~ tho ~irst eluted material, l-[N-(l(S)-carboethoxy-3-phenylpropyl)~ al~nyl]- ~,ondo-octahydrocyclo-penta[blpyrrol0-2~)-ca~boxylic a¢id benzyl ester~
. Hydrogenate 3.0 g o~ N-tl~ carboethoxy-3-phenylpropyl~-(S)-alanyl]-ci~,endo-octahydrocyclopcn~a,~b]pyrrola-2~s)-carboxylic acid benzyl e~ter in 40 ml of ethanol contalning 0.5 9 of 10~ Pd/C. Remov~ the cataly~t by fileration and concentrate th~ f iltrate in vacuo. Add absolute ether to cry~talliæo l-lN ~l(S)-carboethoxy-3-phQnylpropyl)-~S)-alanyl]-cis,endo-octahydrocyclo penta[b~pyrrole-2(S)-carboxylic acid, m.p. 110-112C(d).
E. Add dropwi~o, with stirring, a solution o~
1.3 M hydrochloric acid in ether to tho product of Part D until the mixture i9 pH2. Add 100 ml of ether and continue to ~tir ~or 30 minuteR, then filter to obtain l-[N-l~S)-carboethoxy~3-phenylpropyl)-~S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyrrole-2~S)-carboxylic acid hydrochlorid~.
Method II
-A. Stir a solution of 4.56 9 of N-[l(S)-carboethoxy-3-phenylpropyl]-~S)-alanine, 2.20 g o~ N-hydroxy-succinimida and 3.80 9 of 1-~3-dimethylamino-propyl)-3-ethylcarbodlimide hydrochloride in 30 ml of dimethyl-formamide for 18 hours at roo~ temperature.
Dilute the reaction ~ixture with ethyl acetate and wash the ethyl acetate layer with saturated aqueous sodium chloride. Concantrata thc dried (MqS04) ethyl acetate solution to give N-[l(S)-carboethoxy-3-phenylpropyll-(S)-alanine N-hydroxysuccinimide aster.
B. To a mixture of~ 3.76 g of the product of Part A and 1.55 g of cls,endo-octahydrocyclopenta[b]-pyrrole-2-carboxylic acid in 30 ml of I
dime-thylformamide, add 1.5 ml of triethylamine and stir the resulting mixture at room temperature for 18 hours. Concentrate the reaction mixture ln vacuo and parti-tion between ethyl acetate and H20 (adjusted to pH 4). Wash the ethyl acetate solution with saturated aqueous sodium chloride.
Concentrate the dried (MgS04) ethyl acetate solution ln vacuo and chromatograph the residue on a silica gel (1000 ml) column using /: /: / CHC13/iso-PrOH/7~
NH40H(organic phase). Isolate l-[N-(l(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-clslendo-octahydrocyclo-penta[b]pyrrole-2(S)--carboxylic acid as a foam.
ETHYL CISl EXO-OCTAHYDROCYCLOPENTA[b~PYRROLE-Dissolve 0.4g of ethyl cls,endo-octahydro-cyclopenta[b~pyrrole-2-carboxylate (as prepared in Example 1) in 40 ml of ethanol and 7 ml of triethyl-amine. Re~lux under nitrogen Eor five days. Remove the volatiles ln vacuo and isolate. To obtaln the hydrochloride salt of the product of this example, treat the free base with ethereal HCL.
1-[N-(l(S)-CARBOXY-3-PHENYLPROPYL)-(S)~ LANYL]-CIS, ENDO-OCTAHYDROCYCLOPENTA[b]PYRROLE-2(S)-CARBOXYLIC
ACID AND THE HYDROCHLORIDE SALT THEREOF
A. To a solution of 0.80g of l[N-(l(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-cls,endo-~, . ~ ~
oct~hydrocyclo~nta[b]~yrrol~-2~ c~rboxylie acid fro~
Exala~le 3 in 100 ~1 o meth~nol at 0-5C, ~dd 2.0 ml of 2 . 5N sodiu~ hydroxido $olution ~nd stir at room temperatur~ for 24 hour~. Concen~:ra'c0 thi~ ~olutlon in vacuo and absorb on 350 ml of AG50W-X2 ~o~R~d re~in ( 100-200 mesh, hydrogen form) . Wash the column with w~er until th~ eluat~ i~ neutral and elu~a ~che product with pyr$din~:~20 ~1:24). Concantr~t~ thQ ~luat~ $n vacuo and chromal:ograph on a Lobar RP-8, size B column (~. Merck) u~ing acetonitrile:wdter (2:3) a3 eluant to obtain the title compound of thi~ example as the free amino acid.
B. Treat an ethanol ~olution of the product of Part A with one oquiv~lent of a lN solution o~
ethanolic hydrogen chlaride. Remove th~ 901vent in vacuo at room tempecature to obtain the hydrochlorid~
~alt of the title compound of this example.
multiplet); 2.03-1.18 t6H
multiplet); 1.S7 (lH multiplet).
EXUli'LE Z
1- [N- ( 1 ( R, S ~CAR90ETHOXY-3-PHENYLPROPYI. ) - ( S ) -ALANYL]-CIS,E_DO-:)CTAHYDROCYCLOPENTA[b¦ PYRROLE-2(S)-CAI~OIIYLIC AC~D
A. To a solution of 10.0 9 of ethyl-cis,endo-octahydrocyclopenta [bl pyrrole-2-carboxylate in 400 ml o ethyl acetate add 17.0 g of N-benzyloxycarbonyl ~S)-alanine, N-hydroxy~uccinimide ester. Stir the reaction mixture at room temperatura for 20 hours and concen-t ~
trat~ it in vacuoO Placo tho re~du~ on ~ colu~n ofsillc~ g~l (3000 9, 60-200 ~h) and elu ~ with chlorofor~:ethyl acetata ln:l to obtain l-[N-benzyloxy-c~r~onyl-~S ) -alanyll -ci~,sndo-oetahydrocyclop~nta lb] -pyrrole-2-carboxylic acid, ethyl e3~er, a colorless oil [~1D26-3~.6 (C ~ 0.5, ethanol).
~. To a ~olu~ion of 3.22 9 of l-lN-b~nzyloxy-carbonyl-(S)-alanyl]-c~,endo-octahydrocyclo~enta-[b]pyrrole-2-carboxylic acid, ethyl ester in 150 ~1 of methanol, add 20 ml o~ 205 N sodium hydroxide and stir the mixturs at room temparature for lB hour~.
Concentrate the mixturo under nitrogen, dilute the residue with ice-water and then make the mixtura acidic with concentrated hydrochloric acid. Extract tho aqueous ~olution with ethyl acetate and dry the organic phase over magnesium sulfate. Concentrate the organic pha~e and place it on a column of ~ilica gel (500 9., 60-200 mesh). Elute with chloroform:glacial acstic acid 9:1 and i~olate l-lN-benzyloxycarbonyl-(S)-alanyl]-cis,sndo-octahydrocyclo-penta[b]pyrrole-2(S)-carboxylic acid, as a colorle~ oil, [al D26-26 .4 tC =
0.5, ethanol).
C. Dissolve 1.70 g of l-[N-~enzyloxycarbonyl-(S)-alanyl]-ci~,endo-octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acid in 100 ml of methanol. Add 0.40 9 10~ palladium-on-charcoal and hydrogenate the mixture at atmospheric pressure. ~ilter the mixture and concentrate in vacuo to obta in l-[(S)-alanyl]-cis,endo-oc tahydro-cyc lopenta ~b ] pyrrole~2 t S ) -carboxyl ic ac id .
D. Dissolve l-[(S)-alanyl]-cis,endo-octahydro-cyclopentalblpyrrole-2ts)-carboxylic acid in 100 ml o~
ab~olute m~thanol. Add 1.10 g 2-oxo-~-ph~nylbutyric acld, ethyl ~t~r ~nd 20 ml of 3 Ang~trom ~olecular qlevo pellet~ F and ~tlr th~ re~ulting ~ixture at roo~
te~perature for ei~hteon hour Filt~r th~ re~otion mixture and tr~at the filtrate with 0.68 g sodium cyanoborohydrid0 at roo~ tsmperatur~ for two hour~.
Concentrate the mixture under nitrogen ~nd dilut3 the oil with dilute hydrochloric acid and ~tir at room temperature for one hour. Ab~orb th~ aqu~ou~ solution on 200 ml of a XAD-2 (Xohm ~ Haa~ Co. r~in). El~t~
the re in with 2000 ml of wat~r and then with 2000 ml of methanol. Concentr~te th~ m~thanol ~olution and place the residuo on a column of silica y~l ~400 9, 60-200 me~h) and elute with chlorcform~isopropanol:73 ammonium hydroxida ~lsl~ organic layer) to give 1-[N~ R,S)-carbosthoxy-3-phenylpropyl)-~S)-alanyl]-ci~,endo-octahydrocyclopentalb]pyrrole-2(S)-carboxylic acid, a~ a colorle9~ oil, 1al -5.8 (C~10.6, ethAnol).
l-tN-~1~S)-CAR~OETHOXY-3-PHENYLPROPYL)-~S)-ALANYL]-CIS,ENDO-OCTAHYDROCYCLOPENTA~b]PY~ROL~-2tS)-CARBOXYLIC ACID AND THE HYDRO~HLORID~ SALT THEREOF_ Method I
A. Ci~ ,endo-Oetah~roeyeloE~nta ~b] pYrrole-2-Carboxylie Aeid Hydroehloride Method I Add a 20~ HCl in dioxane ~olution ( 100 ml) to 5 9. of eis,endo~
oetahydrocyclop~nta [b~ pyrrole-2-earboxylic acid. Stir the resulting mixture at room temperature for 30 min.
and then concentrate it in vacuo. Wash the white residue with anhydrou~ ether and dry in vacuo to obtain the tltla co~ound o~ Part A a~ a whito ~olld, m.p.
20g-211, M~thod II Dlssolve 0.2 9 o~ ethyl ci~,endo-oc~hydrocyclopent~[bJpyr~ol~-2-Garboxylat~ (freo ba~a or hydrochlorldo from Example 1 in 20 ml of 6N
hydrochloric acid and reflux over~ight. Cool the reaction mixturo, r~move th~ v~la~ile~ under hLgh vacuum and ob~ain th~ titlc product o~ P~rt Ao B. To 5.0 9 of thc product of Part A, add 50 ml of benzyl alcohol and 50 ml of thionyl chlorida and ~tir at room temperature. Concontrate the reaction mixture ln vacuo and recry~tallize the residu~ rom chloroform/ isopropanol to give benzyl Ci3 ,ando-octahydrocyclopenta[bJDyrrole-2-carboXylate hydrochlorida, m.p. 17S.
C. To 5.5 9 o~ the product of Part ~, add 2.6 g of l-hydroxybenzotria~ole, 5.4 9 of N[l~S)-carboethoxy-3-phenylpropyll-(S)-alanine and 4.0 9 o~ dicyclohexyl-carbodiimide ln 80 ml of dimethyl formamide. Stir the raaction mixtur~ at room temperature ~or 18 hour~.
Filter the reaction mixture, and add ethyl acetata to the filtrate. Extract the ethyl acetate solution (3 X
200 ml) with 5~ aqueou~ codium bicarbonate.
Concentrate the dried ~MqSO4) ethyl acetate solution in vacuo. Chromatograph the residue on a silica gel column (400 g, 60-200 mssh) and eluta with ethyl ace~ate/petroleu~ ether (30-60) 2~ olata, a~ tho ~irst eluted material, l-[N-(l(S)-carboethoxy-3-phenylpropyl)~ al~nyl]- ~,ondo-octahydrocyclo-penta[blpyrrol0-2~)-ca~boxylic a¢id benzyl ester~
. Hydrogenate 3.0 g o~ N-tl~ carboethoxy-3-phenylpropyl~-(S)-alanyl]-ci~,endo-octahydrocyclopcn~a,~b]pyrrola-2~s)-carboxylic acid benzyl e~ter in 40 ml of ethanol contalning 0.5 9 of 10~ Pd/C. Remov~ the cataly~t by fileration and concentrate th~ f iltrate in vacuo. Add absolute ether to cry~talliæo l-lN ~l(S)-carboethoxy-3-phQnylpropyl)-~S)-alanyl]-cis,endo-octahydrocyclo penta[b~pyrrole-2(S)-carboxylic acid, m.p. 110-112C(d).
E. Add dropwi~o, with stirring, a solution o~
1.3 M hydrochloric acid in ether to tho product of Part D until the mixture i9 pH2. Add 100 ml of ether and continue to ~tir ~or 30 minuteR, then filter to obtain l-[N-l~S)-carboethoxy~3-phenylpropyl)-~S)-alanyl]-cis,endo-octahydrocyclopenta[b]pyrrole-2~S)-carboxylic acid hydrochlorid~.
Method II
-A. Stir a solution of 4.56 9 of N-[l(S)-carboethoxy-3-phenylpropyl]-~S)-alanine, 2.20 g o~ N-hydroxy-succinimida and 3.80 9 of 1-~3-dimethylamino-propyl)-3-ethylcarbodlimide hydrochloride in 30 ml of dimethyl-formamide for 18 hours at roo~ temperature.
Dilute the reaction ~ixture with ethyl acetate and wash the ethyl acetate layer with saturated aqueous sodium chloride. Concantrata thc dried (MqS04) ethyl acetate solution to give N-[l(S)-carboethoxy-3-phenylpropyll-(S)-alanine N-hydroxysuccinimide aster.
B. To a mixture of~ 3.76 g of the product of Part A and 1.55 g of cls,endo-octahydrocyclopenta[b]-pyrrole-2-carboxylic acid in 30 ml of I
dime-thylformamide, add 1.5 ml of triethylamine and stir the resulting mixture at room temperature for 18 hours. Concentrate the reaction mixture ln vacuo and parti-tion between ethyl acetate and H20 (adjusted to pH 4). Wash the ethyl acetate solution with saturated aqueous sodium chloride.
Concentrate the dried (MgS04) ethyl acetate solution ln vacuo and chromatograph the residue on a silica gel (1000 ml) column using /: /: / CHC13/iso-PrOH/7~
NH40H(organic phase). Isolate l-[N-(l(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-clslendo-octahydrocyclo-penta[b]pyrrole-2(S)--carboxylic acid as a foam.
ETHYL CISl EXO-OCTAHYDROCYCLOPENTA[b~PYRROLE-Dissolve 0.4g of ethyl cls,endo-octahydro-cyclopenta[b~pyrrole-2-carboxylate (as prepared in Example 1) in 40 ml of ethanol and 7 ml of triethyl-amine. Re~lux under nitrogen Eor five days. Remove the volatiles ln vacuo and isolate. To obtaln the hydrochloride salt of the product of this example, treat the free base with ethereal HCL.
1-[N-(l(S)-CARBOXY-3-PHENYLPROPYL)-(S)~ LANYL]-CIS, ENDO-OCTAHYDROCYCLOPENTA[b]PYRROLE-2(S)-CARBOXYLIC
ACID AND THE HYDROCHLORIDE SALT THEREOF
A. To a solution of 0.80g of l[N-(l(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-cls,endo-~, . ~ ~
oct~hydrocyclo~nta[b]~yrrol~-2~ c~rboxylie acid fro~
Exala~le 3 in 100 ~1 o meth~nol at 0-5C, ~dd 2.0 ml of 2 . 5N sodiu~ hydroxido $olution ~nd stir at room temperatur~ for 24 hour~. Concen~:ra'c0 thi~ ~olutlon in vacuo and absorb on 350 ml of AG50W-X2 ~o~R~d re~in ( 100-200 mesh, hydrogen form) . Wash the column with w~er until th~ eluat~ i~ neutral and elu~a ~che product with pyr$din~:~20 ~1:24). Concantr~t~ thQ ~luat~ $n vacuo and chromal:ograph on a Lobar RP-8, size B column (~. Merck) u~ing acetonitrile:wdter (2:3) a3 eluant to obtain the title compound of thi~ example as the free amino acid.
B. Treat an ethanol ~olution of the product of Part A with one oquiv~lent of a lN solution o~
ethanolic hydrogen chlaride. Remove th~ 901vent in vacuo at room tempecature to obtain the hydrochlorid~
~alt of the title compound of this example.
Claims (13)
1. Process for the preparation of compounds of the general formula IIIa IIIa in the form of the racemic pair or of the individual enantiomers, wherein R6 is hydroxy, lower alkoxy, lower alkenoxy, dilower alkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, aryloxy, arylloweralkoxy, amino, lower alkylamino, dilower alkylamino, hydroxyamino, aryllower alkylamino, or substituted aryloxy or substituted aryllower alkoxy wherein the substituent is methyl, halo or methoxy, which comprises catalytic reduction of compound II
II
wherein R6 is as defined above, followed if desired by the resolution of the racemic mixture to obtain the individual enantiomers.
II
wherein R6 is as defined above, followed if desired by the resolution of the racemic mixture to obtain the individual enantiomers.
2. Process according to claim 1, which further comprises preparing the compound of formula II by the reaction of a halo pyruvate ester (V) V
wherein R6 is as defined above and Hal stands for halogen, with benzyliminocyclopentane.
wherein R6 is as defined above and Hal stands for halogen, with benzyliminocyclopentane.
3. Process according to claim 1 com-prising carrying out the reduction in a solvent, using hydrogen gas and Pd(OH2) on carbon or Pd on carbon.
4. Process according to claim 3 comprising carrying out the reduction step in an alcohol.
5. Process according to any one of claims 2 to 3 comprising carrying out the reaction of the halo pyruvate ester with benzyliminocyclopentane in an inert solvent in the presence of a base at 0-100°C for about 2-8 hours.
6. Process according to any one of claims 2 to 3 comprising the use of bromo pyruvate ester (V).
7. Process according to any one of claims l to 3 comprising the isolation of compound IIIa in the free form or in the form of its ethyl or benzyl ester.
8. In the process for the preparation of a cis, endo-octahydrocyclopenta[b] pyrrole carboxylic acid derivative of general formula (I).
I
and the pharmaceutically acceptable salts thereof, wherein R and R6 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, diloweralkyl-amino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, aryloxy, aryloweralkoxy, amino, lower alkylamino, diloweralkylamino, hydroxyamino, aryl-lower alkylamino, or substituted aryloxy or substi-tuted arylloweralkoxy wherein the substituent is methyl, halo or methoxy;
R1 is hydrogen, alkyl of from 1 to 10 carbon atoms, including branched and cyclic and un-saturated alkyl groups, substituted lower alkyl wherein the substituent is hydroxy, lower alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substi-tuted heteroaryloxy, amino, lower alkylamino, diloweralkylamino, acylamino, arylamino, substituted arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, arylthio, substituted arylthio, carboxy, carbamoyl, lower alkoxycarbonyl, aryl, substituted aryl, aralkyloxy, substituted aralkyloxy, aralkyl-thio, or substituted aralkylthio, wherein the aryl or heteroaryl portion of said substituted aryloxy, heteroaryloxy, arylamino, arylthio, aryl, aralkyloxy or aralkylthio groups is substituted with a group selected from halo, loweralkyl, hydroxy, lower alkoxy, amino, aminomethyl, carboxyl, cyano and sulfamoyl;
R3 is hydrogen, lower alkyl, phenyl lower alkyl, aminomethylphenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl, amino lower alkyl, dimethylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, or lower alkylthio lower alkyl;
starting from a compound of formula (III) the improvement wherein the starting compound is a compound of the general formula (IIIa) as defined in claim 1.
I
and the pharmaceutically acceptable salts thereof, wherein R and R6 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, diloweralkyl-amino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, aryloxy, aryloweralkoxy, amino, lower alkylamino, diloweralkylamino, hydroxyamino, aryl-lower alkylamino, or substituted aryloxy or substi-tuted arylloweralkoxy wherein the substituent is methyl, halo or methoxy;
R1 is hydrogen, alkyl of from 1 to 10 carbon atoms, including branched and cyclic and un-saturated alkyl groups, substituted lower alkyl wherein the substituent is hydroxy, lower alkoxy, aryloxy, substituted aryloxy, heteroaryloxy, substi-tuted heteroaryloxy, amino, lower alkylamino, diloweralkylamino, acylamino, arylamino, substituted arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, arylthio, substituted arylthio, carboxy, carbamoyl, lower alkoxycarbonyl, aryl, substituted aryl, aralkyloxy, substituted aralkyloxy, aralkyl-thio, or substituted aralkylthio, wherein the aryl or heteroaryl portion of said substituted aryloxy, heteroaryloxy, arylamino, arylthio, aryl, aralkyloxy or aralkylthio groups is substituted with a group selected from halo, loweralkyl, hydroxy, lower alkoxy, amino, aminomethyl, carboxyl, cyano and sulfamoyl;
R3 is hydrogen, lower alkyl, phenyl lower alkyl, aminomethylphenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl, amino lower alkyl, dimethylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, or lower alkylthio lower alkyl;
starting from a compound of formula (III) the improvement wherein the starting compound is a compound of the general formula (IIIa) as defined in claim 1.
9. Process according to claim 8 which com-prises selecting a compound of formula (IIIa) suit-able for the preparation of 1-[N-(1(S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]-cis,endo-octahydro-cyclopenta-[b] pyrro1e-2(S)-carboxylic acid.
10. Compound of formula II
wherein R6 is as defined above.
wherein R6 is as defined above.
11. Process according to claim 8 which com-prises selecting a compound of formula (IIIa) suitable for the preparation of the compound of general formula (I) wherein the absolute configur-ation at the carbon atom marked by a single asterisk is the S-configuration.
12. Process according to claim 8 which com-prises selecting a compound of formula (IIIa) suitable for the preparation of the compound of general formula I wherein the absolute configuration at the carbon atoms marked by the double asterisk is most similar to that of natural L-amino acids.
13. Process according to claim 9 wherein the compound of formula (IIIa) is in the S, S, S form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/635,390 US4587258A (en) | 1980-10-23 | 1984-07-30 | Angiotensin-converting enzyme inhibitors |
| US635,390 | 1984-07-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1244041A true CA1244041A (en) | 1988-11-01 |
Family
ID=24547612
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000487583A Expired CA1244041A (en) | 1984-07-30 | 1985-07-26 | Process for the preparation of cis, endo- octahydrocyclopenta¬b|pyrrole-2-carboxylate |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0190224A1 (en) |
| JP (1) | JPS61502818A (en) |
| AU (1) | AU581919B2 (en) |
| CA (1) | CA1244041A (en) |
| DK (1) | DK140886D0 (en) |
| WO (1) | WO1986000896A1 (en) |
| ZA (1) | ZA855659B (en) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3226768A1 (en) * | 1981-11-05 | 1983-05-26 | Hoechst Ag, 6230 Frankfurt | DERIVATIVES OF CIS, ENDO-2-AZABICYCLO- (3.3.0) -OCTAN-3-CARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF, THE MEANS CONTAINING THEM AND THE USE THEREOF |
| DE3431541A1 (en) * | 1984-08-28 | 1986-03-06 | Hoechst Ag, 6230 Frankfurt | CIS, ENDO-2-AZABICYCLOALKAN-3-CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND INTERMEDIATE PRODUCTS IN THEIR PRODUCTION |
| DE3518514A1 (en) * | 1985-05-23 | 1986-11-27 | Hoechst Ag, 6230 Frankfurt | NEW DERIVATIVES OF BICYCLIC AMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF, THE MEANS CONTAINING THEM AND THE USE THEREOF |
| DE3722007A1 (en) * | 1987-07-03 | 1989-01-12 | Hoechst Ag | METHOD FOR PRODUCING BICYCLIC AMINOCARBONIC ACIDS, INTERMEDIATE PRODUCTS OF THIS METHOD AND THE USE THEREOF |
| DE3839127A1 (en) * | 1988-11-19 | 1990-05-23 | Hoechst Ag | PYRROLIDONE-2-CARBONIC ACID DERIVATIVES WITH PSYCHOTROPER EFFECT |
| US5629345A (en) * | 1993-07-23 | 1997-05-13 | Vide Pharmaceuticals | Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure |
| US5965620A (en) * | 1993-07-23 | 1999-10-12 | Vide Pharmaceuticals | Methods and compositions for ATP-sensitive K+ channel inhibition for lowering intraocular pressure |
| GB9716657D0 (en) | 1997-08-07 | 1997-10-15 | Zeneca Ltd | Chemical compounds |
| GB9803226D0 (en) | 1998-02-17 | 1998-04-08 | Zeneca Ltd | Chemical compounds |
| GB9902452D0 (en) | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
| GB9902459D0 (en) | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
| GB9902455D0 (en) | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
| GB9902461D0 (en) | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
| GB9902453D0 (en) | 1999-02-05 | 1999-03-24 | Zeneca Ltd | Chemical compounds |
| GB0000625D0 (en) | 2000-01-13 | 2000-03-01 | Zeneca Ltd | Chemical compounds |
| AU2003290401A1 (en) * | 2003-11-24 | 2005-06-08 | Potluri Ramesh Babu | A process for industrially viable preparation of (s,s,s) phenylmethyl-2-azabicyclo-(3.3.0)-octane-3-carboxylate tosylate |
| NZ548212A (en) | 2003-12-29 | 2010-07-30 | Sepracor Inc | Pyrrole and pyrazole DAAO inhibitors |
| EP1976513B1 (en) | 2006-01-06 | 2016-08-24 | Sunovion Pharmaceuticals Inc. | Cycloalkylamines as monoamine reuptake inhibitors |
| NZ569608A (en) | 2006-01-06 | 2011-09-30 | Sepracor Inc | Tetralone-based monoamine reuptake inhibitors |
| US8097760B2 (en) | 2006-03-31 | 2012-01-17 | Sunovion Pharmacuticals Inc. | Preparation of chiral amides and amines |
| AU2008206039A1 (en) | 2007-01-18 | 2008-07-24 | Sepracor Inc. | Inhibitors of D-amino acid oxidase |
| US7902252B2 (en) | 2007-01-18 | 2011-03-08 | Sepracor, Inc. | Inhibitors of D-amino acid oxidase |
| MX2009012685A (en) | 2007-05-31 | 2009-12-14 | Sepracor Inc | Phenyl substituted cycloalkylamines as monoamine reuptake inhibitors. |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3174844D1 (en) * | 1980-10-23 | 1986-07-24 | Schering Corp | Carboxyalkyl dipeptides, processes for their production and pharmaceutical compositions containing them |
| DE3226768A1 (en) * | 1981-11-05 | 1983-05-26 | Hoechst Ag, 6230 Frankfurt | DERIVATIVES OF CIS, ENDO-2-AZABICYCLO- (3.3.0) -OCTAN-3-CARBONIC ACID, METHOD FOR THE PRODUCTION THEREOF, THE MEANS CONTAINING THEM AND THE USE THEREOF |
| NZ202903A (en) * | 1981-12-29 | 1988-01-08 | Hoechst Ag | 1-- pe pyrrol-2-yl-carboxylic acid derivatives and pharmaceutical compositions |
| IE54551B1 (en) * | 1982-01-22 | 1989-11-22 | Ici Plc | Amide derivatives |
| DE3211676A1 (en) * | 1982-03-30 | 1983-10-06 | Hoechst Ag | NEW DERIVATIVES OF CYCLOALKA (C) PYRROL CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF, THEIR SUBSTANCES AND THE USE THEREOF AND NEW CYCLOALKA (C) PYRROL CARBONIC ACIDS AS THE INTERMEDIATE LEVELS AND METHODS |
| DE3302125A1 (en) * | 1983-01-22 | 1984-07-26 | Boehringer Ingelheim KG, 6507 Ingelheim | AMINO ACID DERIVATIVES, METHOD FOR THE PRODUCTION AND USE THEREOF |
| HU191120B (en) * | 1983-01-31 | 1987-01-28 | Hoechts Ag,De | Process for raceme separation of optically active byciclic imino-alpha-carbonic acid esthers |
| DE3315464A1 (en) * | 1983-04-28 | 1984-10-31 | Hoechst Ag, 6230 Frankfurt | METHOD FOR PRODUCING N-ALKYLATED DIPEPTIDES AND THEIR ESTERS |
| FR2546886B2 (en) * | 1983-06-06 | 1986-05-16 | Adir | DERIVATIVES OF ISOINDOLEDICARBOXYLIC ACIDS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| US4514391A (en) * | 1983-07-21 | 1985-04-30 | E. R. Squibb & Sons, Inc. | Hydroxy substituted peptide compounds |
| DE3333455A1 (en) * | 1983-09-16 | 1985-04-11 | Hoechst Ag, 6230 Frankfurt | METHOD FOR PRODUCING N-ALKYLATED DIPEPTIDES AND THEIR ESTERS |
-
1985
- 1985-07-26 AU AU46718/85A patent/AU581919B2/en not_active Ceased
- 1985-07-26 JP JP60503359A patent/JPS61502818A/en active Pending
- 1985-07-26 ZA ZA855659A patent/ZA855659B/en unknown
- 1985-07-26 WO PCT/US1985/001406 patent/WO1986000896A1/en not_active Application Discontinuation
- 1985-07-26 CA CA000487583A patent/CA1244041A/en not_active Expired
- 1985-07-26 EP EP85903779A patent/EP0190224A1/en not_active Ceased
-
1986
- 1986-03-26 DK DK140886A patent/DK140886D0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU4671885A (en) | 1986-02-25 |
| WO1986000896A1 (en) | 1986-02-13 |
| DK140886A (en) | 1986-03-26 |
| ZA855659B (en) | 1987-03-25 |
| EP0190224A1 (en) | 1986-08-13 |
| DK140886D0 (en) | 1986-03-26 |
| AU581919B2 (en) | 1989-03-09 |
| JPS61502818A (en) | 1986-12-04 |
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