Processes for preparing [2S-(2.alpha.,3a.beta.,7a.beta.)]octahydro-1H-indole-2-carboxylic acid and esters

The processes provide for the preparation of a [2S-(2.alpha., 3a.beta., 7a.beta.)]-octahydro-lH-indole-2-carboxylic ester from an ester precursor by a stereospecific hydrogenation at a pressure below about 400 psi. In addition, the processes provide for the preparation of [2S-(2.alpha.m 3a.beta., 7a.beta.)]-octahydro-lH-indole-2-carboxylic acid or a ester thereof by the hydrogenation of a (2S)-2-carboxyindoline acid precursor.

FIELD OF THE INVENTION 
This invention relates to improved and novel processes for synthesizing 
[2S-(2.alpha., 3a.beta., 7a.beta.)]-octahydro-lH-indole-2-carboxylic acid 
and esters of the formula I: 
##STR1## 
by the stereospecific catalytic hydrogenation of either 
(2S)-2-carboxyindoline, (2S)-2-carbalkoxyindoline or their protic acid 
salts at pressures below about 400 psi. The compounds are useful as 
intermediates in the preparation of inhibitors of angiotensin converting 
enzyme (ACE), which are employed in treating hypertension. 
BACKGROUND OF THE INVENTION 
Processes for preparing individual racemic (2.alpha., 3a.beta., 
7a.beta.)-octahydro-lH-indole-2-carboxylic acid and esters species are 
known. 
U.S. Pat. No. 4,350,704 and Blankley et. al. (J. Med. Chem., 30, 992 (1987) 
disclose that ethyl indole-2-carboxylate, is hydrogenated in a Paar 
apparatus 
##STR2## 
in a reaction medium containing absolute ethanol and concentrated sulfuric 
acid with 10% rhodium on charcoal or 10% rhodium on carbon respectively to 
yield a racemic mixture of ethyl (2.alpha., 3a.beta., 
7a.beta.)-octahydro-lH-indole-2-carboxylate. That racemic mixture is 
resolved through classic multistep procedures i.e. it is then 
de-esterified, benzoylated, fractionally crystallized as an 
.alpha.-methylbenzylamine salt and de-benzoylated to yield individual 
enantiomeric acid species or the mixture is de-esterified, re-esterified, 
fractionally crystallized as a tartrate salt then de-esterified and 
basified to yield individual enantiomeric ester species. 
U.S. Pat. No. 4,508,729 (hereinafter "the '729 Patent") discloses that the 
hydrochloride salt of ethyl (2S)-indoline-2-carboxylate is 
stereospecifically hydrogenated at a high pressure of 50 kg/cm.sup.2 ( 711 
psi). The reaction takes place in water using Palladium on charcoal to 
yield the hydrochloride salt of ethyl 
[2S-(2.alpha.,3a.beta.,7a.beta.)]-octahydro-lH-indole-2-carboxylate. 
The stereospecific hydrogenation of the hydrochloride salt of ethyl 
(2S)-indoline-2-carboxylate is also disclosed in Tetrahedron Lett., 
23(16), 1677 (1982), which authors include all of inventors of the '729 
Patent. The reference, however, only superficially discloses details 
regarding the reaction (i.e., that it occurs in ethanol using palladium on 
carbon to yield the hydrochloride salt of ethyl 
[2S-(2.alpha.,3a.beta.,7a.beta.)-octahydro-lH-indole-2-carboxylic ester 
and that the ester is saponified to the corresponding acid employing a 
sodium hydroxide solution of water and ethanol). 
None of these publications, however, disclose a process for preparing a 
[2S-(2.alpha., 3a.beta., 7a.beta.)]-octahydro-lH-indole-2-carboxylate 
ester from an ester precursor by a stereospecific hydrogenation at a 
pressure below 700 psi. In addition, there is no disclosure of a process 
for preparing 
[2S-(2.alpha.,3a.beta.,7a.beta.)]-octahydro-H-indole-2-carboxylic acid or 
its ester by the hydrogenation of a (2S)-2-carboxyindoline acid precursor. 
SUMMARY OF THE INVENTION 
The invention relates to improved and novel processes for synthesizing 
[2S-(2.alpha.,3a.beta.,7a.beta.)]-octahydro-lH-indole-2-carboxylic ester 
and esters of the formula I 
##STR3## 
wherein R.sub.1 is selected from any of H, C.sub.1-6 straight- or 
branched-chained alkyl and C.sub.4-6 cycloalkyl. 
The ester compounds of formula I are prepared at a Pressure below about 400 
psi by using a precious metal based catalyst containing more than about 5% 
by weight of the precious metal based on the weight of the catalyst to 
hydrogenate either (2S)-2-carboxyindoline, (2S)-2-carbalkoxyindoline or 
their protic acid salts. The hydrogenation is effected in a acidified and 
deoxygenated solvent such as an alcohol, which contains no more than a 
minimal amount of water. The solvent is acidified with a sufficient amount 
of acid such that the added acid is in excess of the amount of acid 
required to protonate the equivalent amount of the reactant indoline 
species. 
The acid compound of formula I is formed either by hydrolyzing the 
aforesaid formed esters or, preferably, by the one step hydrogenation of 
either (2S)-2-carboxyindoline or its protic acid salts.

DETAILED DESCRIPTION OF THE INVENTION 
The invention in its broadest aspects relates to improved and novel 
processes for preparing [(2S-(2.alpha.,3a.beta.,7a.beta.) 
-octahydro-lH-2-carboxylic acid and esters thereof. Depending upon the 
desired end product, slightly different but related process routes may be 
employed. There are two general reaction schemes which may be employed. 
According to the first general reaction scheme the starting compound is an 
acid of the formula III: 
##STR4## 
which when reacted according to the processes of this invention results in 
either the ester or acid of the compound of formula I. In the second 
general reaction scheme the starting material is an ester of the formula 
V: 
##STR5## 
The resulting products are either the ester or acid of the compound of 
formula I depending upon the particular reaction carried out. 
A. First General Reaction Scheme 
Processes according to the first general reaction scheme are described 
hereinafter. 
According to one embodiment of the invention a one step process for 
preparing a compound of the formula (II): 
##STR6## 
comprises reacting an indoline compound of the formula III: 
##STR7## 
with H.sub.2 at a pressure below about 400 psi in a deoxygenated solvent, 
which is a mixture of water and a compound of the formula, R.sub.2 OH, 
where R.sub.2 is selected from any of C.sub.1-6 straight- or 
branched-chained alkyl or C.sub.4-6 cycloalkyl. The reaction is carried 
out in the presence of a precious metal based catalyst containing more 
than about 5% precious metal based on the weight of the catalyst. 
This same compound of formula II may also be prepared in a 2 step procedure 
comprising reacting the indoline compound of formula (III): 
##STR8## 
with H.sub.2 at a pressure below about 400 psi, in a solvent of the 
formula, R.sub.2 OH, which solvent is deoxygenated, contains no more than 
a minimal amount of water not to exceed about 2%, and is acidified with an 
acid (HX) such as HCl, H.sub.2 SO.sub.4, CF.sub.3 CO.sub.2 H or H.sub.3 
PO.sub.4, wherein X is an anion such as CL.sup.-, HSO.sub.4.sup.-, 
CF.sub.3 CO.sub.2 or H.sub.2 PO.sub.4.sup.- in an amount in excess of the 
amount required to protonate the indoline compound. The reaction is 
carried out in the presence of a precious metal based catalyst containing 
more than about 5% by weight precious metal, based on the weight of the 
catalyst. The resulting Product is an acid addition salt of the ester of 
the formula IV: 
##STR9## 
which is then reacted under hydrolytic conditions to produce the desired 
acid of Formula II. 
In the alternative, if the desired end product is the free ester or the 
acid addition salt of the compound of formula IV it may be separated 
before undergoing hydrolysis. 
B. Second General Reaction Scheme 
The compound of formula II may, alternatively, be prepared according to the 
second general reaction scheme by reacting an indoline compound of the 
formula (V): 
##STR10## 
with H.sub.2 at a pressure below about 400 psi, in a solvent of the 
formula, R.sub.2 OH, which solvent is deoxygenated, contains no more than 
a minimal amount of water not to exceed about 2%, and is acidified with an 
amount of acid that is in excess of the amount required to protonate the 
indoline compound. Again, the reaction is carried out in the presence of a 
precious metal based catalyst containing more than about 5% by weight 
precious metal based on the weight of the catalyst. The resulting product 
is the ester compound of formula IV: 
##STR11## 
In the alternative, if the desired end product is the free ester or the 
acid addition salt of the compound of formula IV, it may be separated 
before undergoing hydrolysis. 
In the processes according to the first general reaction scheme, the 
hydrogenation is preferably effected at a pressure below about 120 psi and 
most preferably at about 20 to about 60 psi employing as the catalyst (10% 
rhodium hydroxide on activated carbon, 20% palladium hydroxide on 
activated carbon, or mixed rhodium hydroxide/palladium hydroxide on 
activated carbon (10% rhodium hydroxide/10% palladium hydroxide on 
activated carbon and 5% rhodium hydroxide/5% palladium hydroxide on 
activated carbon) in an aqueous-alcoholic solvent wherein the alcohol is 
methanol or ethanol. 
In the processes according to the second general reaction scheme, the 
hydrogenations are preferably carried out at a pressure below about 50 
psi, most preferably at about 20 to about 50 psi, employing mixed rhodium 
hydroxide/palladium hydroxide catalysts, such as 10% rhodium hydroxide/10% 
palladium hydroxide on activated carbon or 5% rhodium hydroxide/5% 
palladium hydroxide on activated carbon, wherein the alcohol is either 
methanol or ethanol. 
Products from the first general scheme starting from the compound of 
formula III and producing the compound of formula II are isolated from the 
reaction mixture by filtration to remove the catalyst followed by partial 
removal of the solvents and crystallization from mixtures of water and 
organic solvents. Suitable organic solvents include ketones and ethereal 
solvents i.e. acetone, methylethylketone, tetrahydrofuran, glyme and 
diglyme. 
Reaction mixtures giving products of the free ester compounds of general 
formula IV are filtered to remove catalyst and after evaporation of the 
solvent(s) the residue is dissolved in water basified with a suitable 
inorganic base such as an alkali hydroxide (NaOH or KOH) or alkali 
carbonate (K.sub.2 CO.sub.3 or Na.sub.2 CO.sub.3) and the product 
extracted with a suitable organic solvent such as ether, toluene or ethyl 
acetate. 
Examples of other suitable R.sub.2 OH solvents include C.sub.1-6 straight- 
or branched-chained alkyl alcohol (e.g., methanol, ethanol, or 
isopropanol) and C.sub.4-6 cycloalkyl alcohol (e.g., cyclopropylmethanol 
or cyclohexanol). 
Although the preferred catalysts for carrying out the hydrogenations are 
recited above, other precious metal based catalyst may be employed. Other 
such catalysts include iridium on carbon, iridium on alumina powder, 
Palladium on carbon, palladium & platinum on carbon, palladium on alumina, 
palladium on barium carbonate, palladium on barium sulfate, palladium on 
calcium carbonate, palladium on kielselguhr (diatomaceous earth), 
palladium on silica-alumina, palladium on silica gel, palladium on 
strontium carbonate, palladium on tin oxide, Palladium on titania, 
platinum on carbon, platinum on alumina, platinum on barium carbonate, 
platinum on barium sulfate, platinum on kielselguhr (diatomaceous earth), 
platinum on silica-alumina, platinum on silica gel, platinum on tin oxide, 
platinum on titania, rhenium on alumina, rhenium on alumina, rhenium on 
kielselguhr (diatomaceous earth), rhodium on carbon, rhodium on alumina, 
rhodium on kielselguhr (diatomaceous earth), rhodium on silica-alumina, 
rhodium on silica gel, rhodium on titania, ruthenium on carbon, ruthenium 
on alumina, ruthenium on silica-alumina, ruthenium on silica gel, 
ruthenium on titania, silver on alumina and silver on titania. The 
aforesaid precious metal catalyst on carbon are employed either in the 
inactivated or preferably in the activated forms. In addition, suitable 
forms in which the catalysts are employed include powder, granules, 
extrudate, pellets and spheres. 
The preferred catalysts employed in this invention are prepared in dry 
non-pyrophoric forms by known techniques such as described by Pearlman, 
W., Tetrahedron Lett., 17, 1663 (1967). In particular, precious metal(s) 
halide (e g , PdCl.sub.2 and or RhCl.sub.2 3H.sub.2 O) are combined with 
carbon (e.g., DARCO G-60) in deionized water and rapidly stirred while 
being heated to about 80.degree. C. To the heated mixture is added all at 
once an aqueous solution of LiOH and then the heating is terminated. The 
mixture is then stirred overnight before it is filtered and then washed 
with 0.5 v/v% aqueous acetic acid. The collected solid is air dried and 
then dried under vacuum at about 60.degree. C. This catalyst is then 
hydrogenated in situ to activate it. 
The deoxygenation of the hydrogenation medium is effected by an assortment 
of standard techniques such as vacuum degassing, Snyder, L. R. et. al. 
"Introduction to Modern Liquid Chromatography", Wiley, New York, pp 95-97 
and 271 (1974) and Bakalyar, S. R., et. al., J. Chrom., 158 (1978) 277, 
heating as described by Perry, S. G. et. al., "Practical Liquid 
Chromatography," Plenum, New York, p. 174 (1972), ultrasonic treating as 
described by Del' Ova, V. E. et. al., Anal. Chem., 48 992 (1976) and 
Kapustina, O. A. et. al. editors, "Physical Principles of Ultrasonic 
Technology" 1, Plenum, New York (1973) and sparging as described by 
Bakalyar, S. R. et. al., J. Chroma., 158 277 (1978). 
Sparging, the presently most preferred deoxygenating technique, involves 
passing an inert gas, preferably helium, at a flow-rate of about 1000 
ml/minute in about 100 ml of the hydrogenation solvent for about 15 to 
about 30 seconds which removes greater than about 95% of the dissolved 
oxygen. 
In the processes which are carried in the solvent of the formula, R.sub.2 
OH, that contains no more than about 2% of water, the minimization of 
water is effected by using the solvent in its anhydrous form (e.g., 
absolute ethanol or anhydrous methanol). In addition, the amount of water 
that is introduced in the acidification of the solvent is minimized by 
bubbling a dry mineral acid (e.g., HCl) in gaseous form through the 
solvent or by adding a concentrated form of a mineral acid (e.g., 
concentrated sulfuric acid) to the solvent. 
Hydrolytic conditions for converting the octahydroindole carboxylic acid 
ester to the corresponding acid are either (i) basic conditions as 
described by Vincent, M. et. al. Tetrahedron Lett. 23(16), 1677 (1982) and 
in U.S. Pat. No. 4,508,729 to Vincent, M. et. al. (e.g., using relative to 
an amount of the ester an equivalent amount of a base such as 0.9 N 
aqueous sodium hydroxide in an alcohol such as methanol or ethanol (1 ml: 
3 to 4 ml at about room temperature for about 20 hours) or (ii) acidic 
conditions as described Blankley, C. J. et. al., J. Med. Chem., 30, 992 
(1987) and in U.S. Pat. No. 4,350,704 to Hoefle, M. et. al. (e.g., about 
0.01 mole of the ester is heated to reflux in about 15 ml of 15 weight % 
of a mineral acid such as hydrochloric acid for about 4 hours). 
EXAMPLES 
Abbreviations used herein include: TLC, Thin-layer chromatography; HPLC, 
High Pressure Liquid Chromatography; HOAc, glacial acetic acid; MeOH, 
methanol; R.sub.f retardation factor. 
NMR spectra were obtained with a Brucker AM 400 with tetramethylsilane as 
an internal standard. Melting points were determined on a Hoover melting 
point apparatus and are uncorrected. 
The enantiomeric purity of [2S-(2.alpha., 3a.beta., 
7a.beta.)]-octahydro-1H-indole-2-carboxylic acid was determined using 
chiral HPLC: Waters 600 solvent delivery system; Mobile phase: 0.25 mM 
CuSO.sub.4 at 2 ml/min; Column: 25 cm.times.4.5 mm Chiralpak WH.RTM. (J. 
T. Baker) at 50.degree. C.; Detection, Waters 490 UV detector at 240 UV 
detector nm; Sample injection 50 .mu.l of 10 mg/ml sample dissolved in 
water; retention time of the title compound, 17.3 min. 
EXAMPLE 1 
Preparation of 
[2S-(2.alpha.,3a.beta.,7a.beta.)]-octahydro-lH-indole-2-carboxylic acid 
A solution of distilled water (50 ml) and methanol (200 ml) was sparged 
with helium for 1 hour. The deoxygenated solvent was added to the 10% 
rhodium on carbon catalyst (0.50 g on a dry weight basis, 10% load) and 
2S-indoline-2-carboxylic acid (25.0 g, 0.153 mol) in an argon flushed 
autoclave reactor equipped with an internal baffle. The reactor was 
alternately evacuated and pressurized with hydrogen to 60 psi four times 
while stirring the reaction mixture at about 260 rpm. Stirring was stopped 
and the reactor heated to an internal temperature of 60.degree. C. 
Stirring at 485 rpm was begun and additional hydrogen introduced to bring 
the pressure to 80 psi. Hydrogenation was continued for 4.5 hours at 80 
psi 
Heating and stirring were stopped and the reactor allowed to cool to an 
internal temperature of 20.degree.-30.degree. C. The reactor was evacuated 
and argon introduced. The reaction mixture was filtered through a filter 
aid such as diatomaceous earth (DICALITE.RTM.) to remove the catalyst and 
the filter cake washed with methanol. Methanol was removed by rotary 
evaporation at about 40.degree. to 50.degree. C. The residual solid plus 
water was placed under an inert gas (i.e. argon) and 
bis(2-methoxyethyl)ether (diglyme) (50 ml) added. The mixture was heated 
to 100.degree. C. and distilled water (14 ml) added slowly until all solid 
dissolved. Heat was removed and the solution allowed to cool to room 
temperature with stirring. The product began to crystallize while cooling. 
The mixture (under argon) was refrigerated overnight then filtered by 
suction. The collected solid was washed with diglyme (25 ml) and dried in 
air followed by drying in vacuo at 65.degree. C. for 1-2 days to give 3.00 
g of [2S-(2.alpha., 3a.beta., 7a.beta.)]-octahydro-lH-indole-2-carboxylic 
acid (58% yield) as a white solid, mp (265.degree. C.) 
270.degree.-272.degree. C. (dec.). This material eluted as one spot by 
TLC: R.sub.f 0.35 (Whatman MK6F Silica gel plates, 2.5 cm.times.7.5 
cm.times.200 .mu.m layer thickness, eluted with MeOH/CH.sub.2 Cl.sub.2 
/AcOH 50:50L2). Enantiomeric purity.gtoreq.99% enantiomeric excess by 
HPLC. 
EXAMPLE 2 
Preparation of 
[2S-(2.alpha.,3a.beta.,7a.beta.-octahydro-lH-indole-2-carboxylic acid and 
its ethyl ester 
A solution of absolute ethanol (88 ml) and concentrated H.sub.2 (1.84 ml) 
was sparged with argon for 1 hour. The deoxygenated solvent was added to 
the 10% rhodium/10% palladium on carbon catalyst (0.23 g on a dry weight 
basis) and 2S-indoline-2-carboxylic acid (5.00 g, 0.0307 mol) in an argon 
flushed bomb reactor. The reactor was alternately evacuated and 
pressurized with hydrogen to 80 psi five times while stirring the reaction 
mixture at about 260 rpm and the reactor was heated to a temperature of 
60.degree. C. After 45 minutes, the pressure was increased to 120 psi. The 
reaction was allowed to proceed for 3 more hours at about 60.degree. C. 
Heating and stirring were stopped and the reactor was allowed to cool to 
an internal temperature of 20.degree.-30.degree. C. 
An aliquot of the reaction mixture was removed and then filtered through a 
filter aid (DICALITE.RTM.) to remove the catalyst. The filtrate was 
diluted with water and neutralized with solid potassium bicarbonate. The 
pH was then adjusted to about 9 with solid potassium carbonate and the 
aqueous solution was extracted with ethyl acetate. Gas chromatography 
analysis of the extract disclosed the presence of IV, and the analysis by 
TLC (TLC solvent=25% MeOH in CH.sub.2 Cl.sub.2) of organics in the 
reaction mixture and work-up solution disclosed the presence of II. 
EXAMPLE 3 
Preparation of ethyl 
[2S-(2.alpha.,3a.beta.,7a.beta.)]-octahydro-lH-indole-2-carboxylate 
A solution of absolute ethanol (12.5 ml) and concentrated H.sub.2 SO.sub.4 
(0.4 ml) was sparged with argon for 30 minutes. This solution was added to 
the 10% rhodium on carbon catalyst (51 mg) and ethyl 
2S-indoline-2-carboxylate hydrochloride (1.5 g, 6.59 mmol) in an argon 
flushed Parr bottle reactor. The reactor was alternately evacuated and 
pressurized with hydrogen to 40 psi four times, and then shaken while the 
reactor was heated to a temperature of 60.degree. C. The pressure rose to 
49.5 psi. The heating and shaking were stopped after 23.5 hours. 
An aliquot of the reaction mixture was removed and worked-up as described 
in Example 2. Gas chromatographic analysis of the resultant extract 
disclosed a 10% yield of IV. 
An additional 51 mg of the catalyst, which was wet with approximately 5 ml 
of absolute ethanol, was added to the reaction mixture, and the 
hydrogenation was reinitiated at 60.degree. C. for 40 hours. An aliquot of 
this reaction mixture was worked-up as described in Example 2 and the gas 
chromatographic analysis of the resultant extract disclosed a 21% yield of 
the IV. 
EXAMPLE 4 
Preparation of ethyl 
[2S-(2.alpha.,3a.beta.,7a.beta.)]-lH-octahydro-indole-2-carboxylate 
After a solution of absolute ethanol (12.5 ml) and concentrated H.sub.2 
SO.sub.4 (0.4 ml) was sparged as in Example 3, the solution was added to a 
hydrogenation reactor containing 10% rhodium/1% palladium on carbon 
catalyst (51.5 mg) and ethyl 2S-indoline-2-carboxylate hydrochloride (1.5 
g, 6.59 mmol) and reacted as in Example 3 for 23.5 hours. The analysis of 
an aliquot of this reaction mixture disclosed a 32.9% yield of IV. 
An additional 101.6 mg of catalyst was added and the hydrogenation was 
resumed at 60.degree. C. for 44 hours. An analysis of an aliquot of the 
reaction mixture disclosed that the reaction had gone to completion. The 
solvent was removed by evaporation, and the residue was diluted with water 
and neutralized with KHCO.sub.3. Solid K.sub.2 CO.sub.3 was added to pH of 
about 8 and the mixture was extracted 2 times with ethyl acetate. The 
combined organics were washed with brine, dried over Na.sub.2 SO.sub.4, 
filtered and concentrated to yield 0.70 g (54%) of the crude product as an 
oil. .sup.1 H NMR: CDCL.sub.3 .delta.(TMS) 1.1-1.8 (12H,m); 2.0(lH; 
2.2(2HO; 3.1(lH); 3.8(lH); 4.3(2H). 
EXAMPLE 5 
Preparation of [2S-(2.alpha., 3a.beta., 
7a.beta.)]-lH-octahydro-indole-2-carboxylic acid 
The ethyl [2S-(2.alpha., 3a.beta., 
7a.beta.)]-lH-octahydroindole-2-carboxylate compound is hydrolyzed 
according to the method disclosed by Blankley et. al. (J. Med. Chem., 30, 
992, 997 (1987). The hydrolysis is effected as follows: a solution of 2.0 
g (0.01 mol) of the product of Example 4 in 25 ml of 15% HCl is heated at 
reflux for 4 hours and then evaporated to dryness in vacuo to yield after 
recrystallization from acetonitrile/ethyl acetate 1.7 g of the 
hydrochloride salt, mp 186.degree.-187.degree. C. dec. 
The free acid is obtained by dissolving 1.2 g of the hydrochloride in 10 mL 
of H.sub.2 O and adding 2 N NaOH to pH 6.5. The resulting solution is 
evaporated to dryness under reduced pressure and the residue then refluxed 
with 50 mL of acetonitrile and filtered hot. Concentration of the filtrate 
to 10 mL and cooling gives 0.5 g of the titled product. Physical data 
regarding the product is disclosed by Vincent et. al. (Tetrahedron Lett. 
23(16), 1677, 1679, (1982)) as follows: [.alpha.]20.5.degree. .sub.D 
=-47.7, (C =1, MeOH); mp 268.degree.-271.degree. dec.