PROCESS FOR THE SYNTHESIS OF (253A/g.7A^-OCTAHYDRO-lg-INDOLE
CARBOXYLIC ACH) AS AN INTERMEDIATE FOR TRANDOLAPRIL
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority from U.S. Provisional Application Serial No. 61/226,030
filed July 16,2009, which is incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to an improved, stereospecific process for the manufacture
of (25',3a/?,7aS)-octahydro-l//-indole-2-carboxylic acid as a hydrochloride salt, a key
intermediate in the preparation of trandolapril.
BACKGROUND OF THE INVENTION
Trandolapril (1) [CAS Registry No. 87679-37-6] is the ethyl ester prodrug of
trandolaprilat (2) [CAS Registry No. 87679-71-8], and it is a commonly prescribed
cardiovascular drug for controlling and managing hypertension. It functions as an inhibitor of
Angiotensin Converting Enzyme [ACE], which results in lowering blood pressure and is useful
for treatment of heart failure. Trandolapril (1) can be used alone as oral drug. Alternatively, it
can be used in combination with Verapamil, a calcium channel blocker, or with diuretics.
H H
H 1^ H JL J " J ^ N Jk
i f CH3H CO2CH2CH3 H CH3H tOjH
Trandolapril (1) Trandolaprilat (2)
Pharmaceutical utility of trandolapril (1) for use as ACE inhibitor was first disclosed in
US Patent Number 4,933,361. The general approach for preparing trandolapril (1) is based on
the reaction of (2iS',3a/?,7aS)-benzyl octahydro-l/f-mdole-2-carboxylate hydrochloride (3) with
(S)-2-((S)-l-ethoxy-l-oxo-4-phenylbutan-2-ylaiiiino)propanoic acid (4) in the presence of a
variety of coupUng reagents to facilitate amide bond followed by hydrogenolysis of the benzyl
ester. These coupling approaches to make trandolapril (1) are disclosed in US Patent Number
4,933,361 along with WO2004/101515, WO2005051909 WO2006/014916, WO2006/085332,
EP 1724260, WO2007/003947 and US2009/0069574. Thus, it has been demonstrated that
(25',3a/?,7aiS)-benzyl octahydro-l/f-indole-2-carboxylate hydrochloride salt (3) is a key
component in this coupling reaction to manufacture trandolapril (1), and it is typically prepared
from (25',3a/?,7aS)-octahydro-l//-indole-2-carboxylic acid (5) and benzyl alcohol.
^"-yco.c„3Ph J" „ ^ j)
H H CH3H CO2CH2CH3
(3) ^ (4)
r ^ ^ - 'X^CO^H
4 HHCl
ri
(5)
Synthesis of (25',3a/?,7a5)-octahydro-li/-indole-2-carboxylic acid (5), which contains a
^am'-fused octahydroindole ring system, requires correct stereochemistry at the (25)-carboxylic
acid position to afford trandolapril (1). A number of methods have been disclosed for the
synthesis of (5), which involve the use of animal source materials, such as pork liver, or
hazardous chemical reagents, such as bromine and sodium cyanide, or optically active reagents
for resolution of racemic mixtures (which can result in low yields), and are therefore not
amenable for use in large scale preparation.
For instance, the synthesis described by Harming et al.. Tetrahedron Lett. 1983, 24, 5339
is based on Favorski type ring contraction of halogenated ^aw-fused system, but gives a mixture
-2-
of isomers. A different method described by Hemiing et al., in Tetrahedron Lett. 1983, 24, 5343
introduces trans-fusQA ring system efficiently but requires the use of hazardous reagent mercuric
nitrate. Further, synthesis described by Brion et al. US4879392 and Tetrahedron Lett., 1992,33,
4889 uses animal source reagent such pig liver esterase and require further chiral enrichment.
WO 00/40555 and US Patent Number 6,559,318 rely on enzymatic resolution of 2-(2',2'-
methoxy ethyl)cyclohexylamine and reqxoire further chromatographic separation.
Other patents and patent applications such as US Patent Number 4,490,386, EP0088341
and US2009/0069574 describe a method, which uses a-1-phenylethyl amine for resolution of A''-
benzoyl (25,3ai?,7aS)-octahydro-l//-indole-2-carboxylic acid.
On the other hand, WO8601803, WO2004065368 and WO2006/014916 describe the
preparation of (25,3a/?,7a.S)-octahydro-l//-indole-2-carboxylic acid esters via resolution using
10-D-camphor sulfonic acid, hi addition, WO2005/054194 and WO2006/085332 describes the
preparation of (2iS,3ai?,7aS)-octahydro-l//-indole-2-carboxylic acid esters via resolution using (-
)-dibenzoyl-L-tartrate. Finally, EP1724260 utilizes A''-acetoxy-p-acyloxy alanine ester and its
addition to an enamine followed by ring closure.
As described therein, these methods can be inefficient, expensive and do not resuh m
high yield and/or high purity production of (25',3ai?,7aS)-octahydro-l//-indole-2-carboxylic acid
(5). Therefore, in accordance with the present invention, there is a need for a process that is best
suited for large scale preparation of (25,3ai?,7a5)-octahydro-li/-indole-2-carboxylic acid (5) that
will reduce costs, decrease the number of manufacturing steps, decrease hazardous
environmental waste, and increase efficiency of the manufacturing of (25,3ai?,7a5)-octahydrol//-
indole-2-carboxylic acid (5) and ultimately trandolapril.
SUMMARY OF THE INVENTION
The present invention provides commercially scalable processes for the preparation of
(2iS,3a/?,7aLS)-octahydro-lif-indole-2-carboxylic acid hydrochloride (5). Selective N-alkylation
of (lS,2S)-2-[(S)-l-phenylethyl amino]cyclohexyl) methanol (11) with ethyl bromoacetate (12)
was performed with sodium bicarbonate in acetonitrile to give compound (13). The hydroxyl
functionality in compound (13) is then converted to methanesulfonate ester to afford compound
(14). Subsequent treatment of compound (14) with a base, such as, but not limited to, sodium
-3-
tert-butoxide in tetrahydrofuran or mixtvires of tetrahydrofuran produces a trans-fused
octahydroindole ring system (15) with the correct stereochemistry at the (2S)-carboxylic ester
position, as the major isomer. The N-a-methylbenzyl group in (2S,3aR,7aS)-Ethyl 1-((S)-1-
phenylethyl)octahydro-lH-indole-2-carboxylate (15) is cleaved by hydrogenolysis using
palladium on carbon or palladium hydroxide on carbon in the presence of hydrogen gas, ethanol,
and hydrogen chloride, to afford the hydrochloride salt of compound (16). Thereafter, the
hydrochloride salt of compound (16) is subjected to acid hydrolysis by the incorporation of
hydrochloric acid to provide the (2S,3aR,7aS)-octahydro-lH-indole-2-carboxylic acid (5) as its
hydrochloride salt in good overall yield (See Figure 5). Compound (5) is isolated by
crystallization from acetonitrile.
In another embodiment, (lS,2S)-2-[(S)-l-phenylethyl amino]cyclohexyl) methanol (11)
is produced from a starting material comprising ethyl 2-oxocyclohexane carboxylate (6). This
embodiment comprises reacting ethyl 2-oxocyclohexane carboxylate (6) with (S)-(-)-lphenylethylamine
(7) in the presence of toluene to produce (5)-Ethyl 2-(lphenylethylamino)
cyclohex-l-enecarboxylate (8). Further, reduction of the amine (8) with
sodium borohydride in the presence of isobutyric acid will produce (IR, 2S)-Ethyl 2-((S)-lphenylethylamino)
cyclohexanecarboxylate (9), as illusfrated in Figure 4. Additionally, the
conversion of the amine (8) to the c/j'-cyclohexane derivative (9) is fiuther treated with hydrogen
bromide and ethyl acetate in propionic acid to create the hydrobromide salt of the ciscyclohexane
derivative (9). The production of the c/.s-cyclohexane derivative (9) is followed by
epimerization of the chiral center adjacent to the ethyl ester fiinctionality using sodium tertbutoxide
to afford the /raw-cyclohexane derivative (10) as a major diastereomer. After
conversion to /ra«5-cyclohexane derivative (10), the compound is subjected to reduction of the
ester functionality in compound (10), using potassium borohydride in the presence of lithium
chloride, to yield (lS,2S)-2-[(S)-l-phenylethyl amino]cyclohexyl)methanol (11). Generally, the
conversion from compound (10) to compound (11) may incorporate tetrahydrofiiran as a cosolvent
and may be refluxed to afford the desired compound (11) in good overall yield.
In a further embodiment, the present invention provides commercially scalable processes
for the preparation of (25,3ai?,7a5)-octahydro-li7-indole-2-carboxylic acid hydrochloride (5).
Selective N-alkylation of (lS,2S)-2-[(S)-l-phenylethyl amino]cyclohexyl) methanol (11) with
ethyl bromoacetate (12) was performed with sodium carbonate in acetonitrile to give compound
-4-
(13). The hydroxyl functionality in compound (13) is then converted to methanesulfonate ester to
afford compound (14). Subsequent treatment of compound (14) with a base, such as, but not
limited to, sodium tert-butoxide in tetrahydrofuran or mixtures of tetrahydrofuran produces a
trans-fused octahydroindole ring system (15) with the correct stereochemistry at the (2S)-
carboxylic ester position, as the major isomer. The N-a-methylbenzyl group in (2S,3aR,7aS)-
Ethyl l-((S)-l-phenylethyl)octahydro-lH-indole-2-carboxylate (15) is cleaved by hydrogenolysis
using palladium on carbon or palladium hydroxide on carbon in the presence of hydrogen and
ethanol, to afford the free base form of compound (16). Thereafter, the free base form of
compound (16) is subjected to acid hydrolysis by the incorporation of hydrochloric acid to
provide the (2S,3aR,7aS)-octahydro-lH-indole-2-carboxylic acid (5) as its hydrochloride salt in
good overall yield (See Figure 2). Compound (5) is isolated by crystallization from acetonitrile.
hi an additional embodiment, (lS,2S)-2-[(S)-l-phenylethyl amino]cyclohexyl) methanol
(11) is produced from a starting material comprising ethyl 2-oxocyclohexane carboxylate (6).
This embodiment comprises reacting ethyl 2-oxocyclohexane carboxylate (6) with (S)-(-)-lphenylethylamine
(7) in the presence of a catalyst, ytterbium trifluoromethanesulfonate, and
heptane to produce (5)-Ethyl 2-(l-phenylethylamino)cyclohex-l-enecarboxylate (8). The next
step is reduction of the amine (8) with sodium acetoxyborohydride in the presence of a
acetonitrile produce (IR, 2S)-Ethyl 2-((S)-l-phenylethylamino)cyclohexanecarboxylate (9), as
illustrated in Figure 1. The production of the cw-cyclohexane derivative (9) is followed by
epimerization of the chiral center adjacent to the ethyl ester functionality using sodium tbutoxide
to afford /rara-cyclohexane derivative (10) as a major diastereomer. Reduction of the
ester functionality in compound (10), using lithium borohydride yields(15',25)-2-[(5)-lphenylethyl
amino] cyclohexyl)methanol (11) in good overall yield, which is subsequently
purified by chromatography.
In yet another embodiment, (25',3a/?,7a5)-benzyl octahydro-li7-indole-2-carboxylate
hydrochloride salt (3), is produced using a starting material of crystalline ((15,25)-2-((5)-lphenylethylamino)
cyclohexyl)methanol (11). The first step of the process involves reaction
with a catalyst including palladium on carbon in the presence of methanol to produce ((15,25)-2-
aminocyclohexyl)methanol (17). Compound (17) is subjected to treatment with sodium cyanide
in the presence of formaldehyde to produce compound (18). Subsequently, compound (18) is
first reacted with trimethylsilyl chloride, and then the product of that reaction is treated with
-5-
benzyl methoxychloride to produce compound (19). Further, compound (19) is subjected to
three sequential reactions to produce compound (20) as illustrated m Figure 3. Specifically,
compound (19) is first subjected to treatment with hydrochloric acid. Subsequently,
methanesulfonyl chloride is added to the reaction mixtvire. Thereafter, potassium hydroxide is
added to the reaction to produce compound (20). After compound (20) is produced, the
compound is treated with aqueous mineral acid to produce the hydrochloride salt of compound
(5).
BRIEF DESCRIPTION OF THE DRAWINGS
Other advantages of the present invention will be readily appreciated, as the same
becomes better understood by reference to the following detailed description when considered in
cormection with the accompanying drawings, wherein:
Figure 1 illustrates a process for making (liS',25)-2-[(5)-l-phenylethyl amino]cyclohexyl)
methanol (11), comprising the use of ytterbium trifluoromethanesulfonate as a catalyst.
Figure 2 illustrates a first process for making (25',3a/?,7aS)-octahydro-l//-indole-2-
carboxylic acid (5), wherein intermediate compoimd (16) comprises the free base form of the
compound.
Figure 3 illustrates the process for making (2iS',3ai?,7aS)-octahydro-l//-indole-2-
carboxylic acid (5) by using (15',25)-2-[(5)-l-phenylethyl aminojcyclohexyl) methanol (11) as a
starting material.
Figure 4 illustrates a process for making (15',25)-2-[(5)-l-phenylethyl amino]cyclohexyl)
methanol (11), comprising the use of toluene as a solvent, without the incorporation of a catalyst.
Figure 5 illustrates the process for making (2iS',3ai?,7aS)-octahydro-l//-indole-2-
carboxylic acid (5) wherein intermediate compound (16) comprises the hydrochloride salt form
of the compound.
Figure 6 depicts a chart showing the various embodiments of the current invention and
how they compare to methods of producing (25',3ai?,7aS)-benzyl octahydro-li/-indole-2-
carboxylate hydrochloride salt (3) disclosed in the prior art. Specifically, Figure 6 outlines the
-6-
differences between the current methods and previous methods by depicting the reduction in
total steps required for production of compound (3) in all embodiments and the efficiencies
gained fi^om the reduction of steps.
DETAILED DESCRIPTION
The present invention provides for the preparation of (25',3ai?,7a5)-octahydro-li?-indole-
2-carboxylic acid hydrochloride (5) and is based on a chiral auxiliary induced diastereoselective
intra-molecular ring-closure strategy. Multiple approaches may be used in the development of
compound (5), all of which are encompassed by the current invention. Specifically, one
approach may incorporate the use of a catalyst, whereas another embodiment may rely on an acid
solvent to produce the compound. In one embodiment of the present invention, the auxiliary
employed is (5)-(-)-l-phenylethylamine (7) in the presence of a catalyst. This allows setting of
the trans-fused absolute chirality in octahydroindole bicyclic ring system based upon
modification of the literature as described in Figure 1 [See CimareUi et al., Tetrahedon
Asymmetry 1994, 5, 1455 and J. Am. Chem. Soc. 1996,118, 5502], but more importantly, it
allows introduction of correct stereochemistry at the (25)-carboxylic acid position as described in
Figure 2. In another embodiment of the present invention, the auxiliary employed is (5)-(-)-lphenylethylamine
(7), in the presence of a solvent, without incorporating a catalyst based upon
modification of the literature as described in Figure 4 [See Xu D et al., Tetrahedron Asymmetry,
Vol. 8, No. 9, pp/1445-51, 1997].
1. Catalyst Approach
In one embodiment, the process of the present invention may utilize ethyl 2-
oxocyclohexane carboxylate (6) to prepare (15',25)-2-[(5)-l-phenylethyl
amino]cyclohexyl)methanol (11) as described in Figure 1 by modification of synthesis methods
found in the literature [Tetrahedon Asymmetry 1994, 5, 1455 and J Am. Chem. Soc. 1996,118,
5502]. Thus, ethyl 2-oxocyclohexane carboxylate (6) may be treated with (5)-(-)-lphenylethylamine
(7) in the presence of a Lewis acid catalyst in aprotic solvents including, but
not limited to, heptanes, or toluene, produced (5)-Ethyl 2-(l-phenylethylamino)cyclohex-lenecarboxylate
(8). As described in Hayashi et al., J. Am. Chem. Soc, 1996, 118, 5502-03, the
-7-
catalyst may be ytterbium trifluoromethanesulfonate [Yb(CF3 803)3, also known as Yb(0Tf)3].
Reduction of the amine (8) with selective reducing agents, such as, but not limited to, sodium
acetoxyborohydride or iV-Selectride in the presence of a co-solvent, may be used to produce (IR,
2S)-Ethyl 2-((S)-l-phenylethylamino)cyclohexanecarboxylate (9), as illustrated in Figure 1. The
production of the c/5-cyclohexane derivative (9) is followed by epimerization of the chiral center
adjacent to the ethyl ester functionality using a base, including, but not limited to, sodium tbutoxide
or lithium hexamethyldisilazide, affording the /ra«5-cyclohexane derivative (10) as a
major diastereomer. Reduction of the ester functionality in compound (10), using reagents such
as, but not limited to, lithium borohydride or potassiimi borohydride, yielded {\S,2S)-2-[(S)-lphenylethyl
amino]cyclohexyl)methanol (11) in good overall yield, which may be purified by
chromatography and isolated as a crystalline solid. Given the inexpensive and readily available
starting materials, the process described herein for the development of (15,25)-2-[(lS)-lphenylethyl
amino]cyclohexyl)methanol (11) is considered a desirable ahemative.
2. Solvent Approach
In another embodiment, the present invention may utilize ethyl 2-oxocyclohexane
carboxylate (6) to prepare (lS,2S)-2-[(S)-l-phenylethyl amino]cyclohexyl)methanol (11) as
described in Figure 4 by modification of methods of synthesis using an aprotic solvent to
produce an amine [See Xu D et al., Tetrahedron Asymmetry, Vol. 8, No. 9, pp/1445-51, 1997].
The current embodiment may comprise reacting ethyl 2-oxocyclohexane carboxylate (6) with
(S)-(-)-l-phenylethylamine (7) in the presence of an aprotic solvent including, but not limited to,
toluene and acetonitrile, to produce (5)-Ethyl 2-(l-phenylethylamino)cyclohex-l-enecarboxylate
(8). The ratio of compound (6) to compound (7) generally ranges from approximately 10:1 to
approximately 1:10. In one embodiment, the ratio of compound (6) to compound (7) ranges
from approximately 5:1 to approximately 1:5. In another embodiment, the ratio of compound (6)
to compound (7) ranges from approximately 2:1 to approximately 1:2. In an additional
embodiment, the ratio of compound (6) to compound (7) comprises approximately 1:1.05.
The modification encompassed within the current embodiment provides unique benefits
not experienced with the methods incorporating a Lewis acid catalyst such as ytterbium
trifluoromethanesulfonate [Yb(CF3S03)3, also known as Yb(OTf)3], as previously discussed.
-8-
The current embodiment eliminates the need for the incorporation of a Lewis acid catalyst
Yb(0Tf)3. Due to the fact that ytterbium compounds are known to be toxic, the elimination of
this catalyst from the current embodiment provides an improved safety profile for the process, as
well as a more cost-effective alternative to other methods.
Further, reduction of the amine (8) with selective reducing agents, such as, but not
limited to, sodium borohydride or N-Selectride in the presence of an acid and a co-solvent, can
be used to produce (IR, 2S)-Ethyl 2-((S)-l-phenylethylamino)cyclohexanecarboxylate (9), as
illustrated in Figure 4. The acid may include, but is not limited to, acetic acid, isobutyric acid,
pivalic acid, benzoic acid, trifluouroacetic acid, and phenylacetic acid. The acid is generally
added to the reaction at a temperature ranging from approximately -20° C to approximately 40°
C, and m another embodiment, the reaction temperature ranges from approximately 0° C to
approximately 20° C. Additionally, the co-solvent may include, but is not limited to, toluene and
acetonitrile. The co-solvent is generally maintained at a temperature ranging from
approximately -10° C to approximately 10° C, and in another embodiment, the reaction
temperature ranges from approximately -2° C to approximately 2° C. Further, the addition of a
co-solvent to the reaction may be accompanied by the addition of a base, including, but not
limited to, sodium hydroxide, to increase the pH of the reaction to a pH in the range of
approximately 8 to approximately 10. In another embodiment, the base is added to achieve a pH
of approximately 9.
One skilled in the art will appreciate that the c/j'-cyclohexane derivative (9) may be
produced by the incorporation of any of the acids and co-solvents described herein, in an
acceptable yield. However, use of the combination of toluene as a co-solvent with isobutyric
acid offered similar yields and an improwed cis/trans ratio compared to pivalic acid, while also
providing easier handling wdth isobutyric acid compared to pivalic acid. Therefore, the
embodiment illustrated in Figure 4 provides additional benefits due to the fact that the toluene
used in the conversion of ethyl 2-oxocyclohexane carboxylate (6) to the amine (8) provides the
necessary co-solvent needed in combination with isobutyric acid to convert the amine (8) to the
c/5-cyclohexane derivative (9). The ability to use the same solvent in the conversion from
compound (6) to compound (8) and the conversion of compound (8) to compound (9) provides
for greater efficiencies, decreasing the number of solvents required and providing a more costeffective
alternative.
-9-
The conversion of the amine (8) to the cw-cyclohexane derivative (9) may be performed
with excellent yield and optical purity if the reaction is further treated with hydrogen bromide
and ethyl acetate in propionic acid to create the hydrobromide salt of the cw-cyclohexane
derivative (9). It is further contemplated that the treatment of the c/^-cyclohexane derivative
may be performed in the presence of hydrogen bromide gas as well. The production of
compound (9) results in a diastereomeric excess/enantiomeric excess (de/ee) of approximately
85% or greater. In one embodiment, the diastereomeric excess/enantiomeric excess of the ciscyclohexane
derivative comprises approximately 95% or greater. It was also discovered that
further treatment of cw-cyclohexane derivative (9) with acetonitrile may increase the
diastereomeric excess/enantiomeric excess to approximately 99% or greater. Additionally, after
treatment with acetonitrile, the overall yield of cw-cyclohexane derivative (9) ranges from
approximately 75% to approximately 85%. The treatment with acetonitrile is generally
conducted at a temperature ranging from approximately -10° C to approximately 0° C. In an
additional embodiment, the temperature ranges from approximately -2° C to approximately 2° C.
As such, the current invention is a modification of the teachings of Xu et al., as it relates to the
conversion of the amine (8) to the cw-cyclohexane derivative (9).
The conversion of the amine (8) to the cw-cyclohexane derivative (9) as disclosed in the
current embodiment, provides benefits not previously experienced. The previous embodiment
disclosed the use of sodium acetoxyborohydride in the presence of acetic acid and acetonitrile to
convert the amine (8) to (IR, 2S)-Ethyl 2-((S)-l-phenylethylamino) cyclohexanecarboxylate (9).
The previous embodiment is a modification and improvement of the method as taught by
CimareUi et al.. Tetrahedron Asymmetry, Vol. 5, No. 8, pp. 1455-1458, 1994]. Although the
method of the previous embodiment may be used to produce the cw-cyclohexane derivative (9),
as depicted in Figure 1, the previous embodiment is limited in the fact that it may require
chromatographic purification to isolate the desired diastereomer, as previously discussed. The
process of chromatographic purification is inefficient, especially as applied to production scale
activities. Therefore, the modifications and improvements incorporated in the conversion of the
amine (8) to the cw-cyclohexane derivative (9) as illustrated in Figure 4 provide substantial
efficiency benefits by not requiring chromatographic purification.
As an alternative approach for the conversion of compound (8) to compound (9), the use
of a hydrogenation step may be utilized. The inventors of the current invention have also found
-10-
that modification of the processes described in WO 2009/015166 to Santella et al., which is fully
incorporated herein by reference, may be used for the conversion from compound (8) to ciscyclohexane
derivative (9). Specifically, rather than the use of an acid such as isobutyric acid in
the presence of an acid, compound (8) may be subjected to catalytic hydrogenation to produce
compoxmd. The catalytic hydrogenation may generally include the incorporation of a catalyst
including, but not limited to, carbon supported nanoparticles (Pt/C), and the use of a
hydrogenating agent mcluding, but not limited to, acetic acid. The conversion of compound (8)
to compound (9) may also incorporate the use of an additional compound, comprising ethanol to
further support the hydrogenation of compound (8). The hydrogenation reaction yields the major
aminoester diastereomer, with only a small amount of the minor aminoester diastereomer. The
hydrogenation reaction described herein may provide advantages in the form of better
stereoselectivity and greater cost effectiveness.
The production of the cw-cyclohexane derivative (9) is followed by epimerization of the
chiral center adjacent to the ethyl ester functionality using a base, including, but not limited to,
sodium tert-butoxide or lithium hexamethyldisilazide, to afford the /raw-cyclohexane derivative
(10) as a major diastereomer. The epimerization reaction is typically performed in the presence
of one or more additional compounds including, but not limited to, tetrahydrofuran and tertbutanol.
Generally, the conversion from compound (9) to compound (10) is performed at a
temperature ranging from approximately -5° C to approximately 35° C. In one embodiment, the
temperature is in the range of approximately 6° C to approximately 25° C. The conversion of
cw-cyclohexane derivative (9) to the /ra«5-cyclohexane derivative (10) generally results in a
yield of the tram-isomer of approximately 75% to approximately 85%, while the remaining
approximately 15% to approximately 25% comprises the cw-isomer. It should be noted that the
hydrobromide salt of cw-cyclohexane derivative (9) may also be converted to the free base form
of the compound prior to converting to compound (10) by reacting the compound with sodixom
carbonate and heptane.
The current embodiment has modified and improved the teachings of the prior art, as
disclosed in Hayashi et al., J. Am. Chem. Soc, 1996, 118, 5502-03, by additionally incorporating
a recapture and recycling step, such that the portion of cis-cyclohexane derivative (9) that is not
converted intoVaw-cyclohexane derivative (10) may be recaptured and re-inserted into the
reaction to further increase the yield of the trans-isomer, as illustrated in Figure 4. The recycling
-11-
of the unreacted cw-cyclohexane derivative (9) generally incorporates the use of hydrogen
chloride in ethanol to transform the /rara-cyclohexane derivative (10) and cw-cyclohexane
derivative (9) into the hydrochloride salt of trans-cyclohQxane derivative (10), with a yield of
approximately 60% to approximately 70%, and a stereoselectivity of approximately 99% or
greater of the trans-isomer. With the incorporation of the recapture and recycling process, the
yield of the rra«5-cyclohexane derivative (10) may be increased to approximately 99%) or
greater. The Hayashi reference does not teach that the c/5-cyclohexane derivative (9) remaining
after the partial conversion to /ra«5-cyclohexane derivative (10) may be recycled and
reintroduced into the reaction. Therefore, the yields achieved with the current method are
significantly greater than those attained according to the Hayashi method, and the current
embodiment is an improvement over the prior art.
After conversion to rra«5-cyclohexane derivative (10), the compound is subjected to
reduction of the ester fimctionality in compound (10), using reagents such as, but not limited to,
potassium borohydride in the presence of lithium chloride, to yield (lS,2S)-2-[(S)-l-phenylethyl
amino]cyclohexyl)methanol (11). Generally, the conversion from compound (10) to compound
(11) may incorporate tetrahydrofiaran as a co-solvent and may be refluxed to afford the desired
compound (11) in good overall yield. It should be noted that compound (10) may be converted
to the free base from the hydrochloride salt by reaction with sodium carbonate prior to
conversion to compound (11).
The conversion from /raw-cyclohexane derivative (10) to (lS,2S)-2-[(S)-l-phenylethyl
amino] cyclohexyl)methanol (11) is a modification and improvement over prior art methods as
disclosed in Schinnerl et al., Eur. J. Org. Chem., 2003, 721-726. The current embodiment
incorporates the use of potassium borohydride in the presence of lithium chloride, rather than
lithium borohydride. The inventors surprisingly found that the overall yield of compound (11)
was similar to previous methods; however, the use of potassium borohydride provides substantial
cost savings, resulting in greater cost-effectiveness of the method.
-12-
3. Process for Generating (25'^aif,7a5)-octahydro-l/r-indole-2-carboxylic acid (5)
a. Under the Catalyst Approach
The (15',25)-2-[(5)-l-phenylethyl amino]cyclohexyl)methanol (11) compound produced
by the steps previously described under the catalyst approach may further be incorporated into
the process illustrated in Figure 2. Selective A^-alkylation of (15',25)-2-[(5)-l-phenylethyl
amino] cyclohexyl) methanol (11) with ethyl bromoacetate (12) was performed with a base such
as, but not limited to, sodium carbonate, sodium bicarbonate, or potassium carbonate, in
acetonitrile or tetrahydrofuran to give compound (13). The hydroxyl functionality in compound
(13) was converted to a leaving group, such as, but not limited to, methanesulfonate ester,
trifluoromethane sulfonate ester, chloride, bromide, or iodide, to afford compound (14). The
conversion to a leaving group may be reacted in the presence of triethylamine and
dichloromethane.
It should be noted that compound (14) as illustrated in Figure 2 comprises the resulting
compound when the hydroxyl functional group of compound (13) is converted to a
methanesulfonate ester. However, compovmd (14) may exist in alternative embodiments without
departing from the scope of the current invention. Specifically, compound (14) may exist
according to following structure:
H
^^•^•^'''y^N R4
H
(14)
wherein Rl and R2 are each selected from the group consisting of alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl, alkylsulfinyl, and arylsulfmyl, each of which is substituted with aryl,
heteroaryl, or cycloalkyl; R3 is a suitable leaving group selected from the group consisting of
mesylate, triflate, tosylate, methanesulfonate ester, trifluoromethane sulfonate ester, chloride,
bromide, and iodide; and R4 is selected from the group consisting of ester, nitrile, alkenyl,
alkynyl, sulfonyl, aryl, and heteroaryl.
-13-
Treatment of compound (14) with a base, such as, but not limited to, sodium tertbutoxide,
sodium hydride, or lithium diisopropylamide, in solvents, such as, but not limited to,
tetrahydrofuran or mixtvires of tetrahydrofiiran and heptanes, produced a ^aw-fused
octahydroindole ring system (15) with the correct stereochemistry at the (25)-carboxylic ester
position, as the major isomer. Generally, m order for the reaction to proceed with acceptable
yields, compound (15) may be purified by column, chromatography prior to any further
processing. The iV-a-methylbenzyl group in (25',3a/?,7aS)-Ethyl l-((5)-l-phenylethyl)octahydrol//-
indole-2-carboxylate (15) is cleaved by hydrogenolysis using metal catalysts, such as, but not
limited to, palladium on carbon or palladium hydroxide on carbon, in the presence of hydrogen
gas and ethanol to afford compound (16). Subsequently, compound (16) was subjected to acid
hydrolysis to provide the (25,3 a/?,7aS)-octahydro-l//-indole-2-carboxylie acid (5) as its
hydrochloride salt in good overall yield.
b. Under the Solvent Approach
The current embodiment also encompasses a new process for the development of
(2S,3aR,7aS)-octahydro-lH-indole-2-carboxylic acid (5), using the starting material (lS,2S)-2-
[(S)-l-phenylethyl amino]cyclohexyl)methanol (11) produced in the previous steps under the
solvent approach, as illustrated in Figure 5. Selective N-alkylation of (1 S,2S)-2-[(S)-lphenylethyl
amino]cyclohexyl) methanol (11) with ethyl bromoacetate (12) was performed with
a base such as, but not limited to, sodium bicarbonate, sodium carbonate, or potassium
carbonate, in acetonitrile to give compound (13). It should be noted that it is also possible to
incorporate ethyl chloroacetate instead of ethyl bromoacetate (12) without departing from the
scope of the current invention. The hydroxyl functionality in compound (13) was converted to a
leaving group, such as, but not limited to, methanesulfonate ester, trifluoromethane sulfonate
ester, chloride, bromide, or iodide, to afford compound (14). The conversion to a leaving group
may be reacted in the presence of triethylamine and dichloromethane. The conversion from
compound (13) to compound (14) generally incorporates a temperature ranging from
approximately -10° C to approximately 20° C. In another embodiment, the conversion of
compound (13) to compound (14) is performed at a temperature ranging from approximately 0°
C to approximately 10° C. Further, the reaction is allowed to proceed for a sufficient amount of
time, generally not less than one hour.
-14-
It should be noted that compound (14) as illustrated in Figvire 4 comprises the resulting
compound when the hydroxyl functional group of compound (13) is converted to a
methanesulfonate ester. However, compound (14) may exist in alternative embodiments without
departing from the scope of the current invention. Specifically, compound (14) may exist
according to following structure:
^ - l ^ N R4
H
(14)
wherein Rl and R2 are each selected from the group consisting of alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl, alkylsulfinyl, and arylsulfinyl, each of which is substituted with aryl,
heteroaryl, or cycloalkyl; R3 is a suitable leaving group selected from the group consisting of
mesylate, triflate, tosylate, methanesulfonate ester, trifluoromethane sulfonate ester, chloride,
bromide, and iodide; and R4 is selected from the group consisting of ester, nitrile, alkenyl,
alkynyl, sulfonyl, aryl, and heteroaryl.
Treatment of compound (14) with a base, such as, but not limited to, sodium tertbutoxide,
sodium hydride, or lithium diisopropylamide, in solvents, such as, but not limited to,
tefrahydrofliran or mixtures of tetrahydrofuran and heptanes, produced a frans-fused
octahydroindole ring system (15) with the correct stereochemistry at the (2S)-carboxylic ester
position, as the major isomer. The yield of (2S)-isomer for compound (15) generally ranges
from about 90% to about 99%, and the yield of (2R)-isomer generally ranges from about 1% to
about 10%. In another embodiment, the ratio of (2S)-isomer to (2R)-isomer of compound (15) is
approximately 95:5. Additionally, the conversion of compound (14) is generally performed at a
temperature ranging from approximately 20° C to approximately 65° C, and the reaction is
allowed to proceed for a sufficient amount of time, generally not less than one hour.
-15-
Compared to prior art methods and the previous embodiments described herein, the
production of compound (15) according to this embodiment does not require purification by
chromatography, thus providing significant benefits over previous methods. The N-amethylbenzyl
group in (2S,3aR,7aS)-Ethyl l-((S)-l-phenylethyl)octahydro-lH-indole-2-
carboxylate (15) is cleaved by hydrogenolysis using metal catalysts, such as, but not limited to,
palladium on carbon or palladium hydroxide on carbon in the presence of hydrogen gas, ethanol,
and hydrogen chloride, to afford the hydrochloride salt of compound (16). The overall yield of
compound (16) ranges from approximately 35% to approximately 45%, after a five-step process
v^herein compound (10) is used as the starting material. Incorporating compound (6) as the
starting material, and using the solvent approach as described herein, the yield of compound (6)
ranges firom approximately 15% to approximately 25%, after an eight-step process.
Thereafter, the hydrochloride salt of compound (16) is subjected to acid hydrolysis by the
incorporation of an acid including, but not limited to, 6 N hydrochloric acid to provide the
(2S,3aR,7aS)-octahydro-lH-indole-2-carboxylic acid (5) as its hydrochloride salt in good overall
yield (See Figure 5). It should be noted that compound (5) is isolated by crystallization fi-om a
solvent including, but not limited to, acetonitrile. Additionally, the yield of the hydrochloride
salt of compound (5) compared to the amount of compound (16) ranges fi-om approximately 80%
to approximately 90%.
Subsequently, crystallized compound (5) may be subjected to esterification to produce
(25',3a/?,7aiS)-benzyl octahydro-liif-indole-2-carboxylate hydrochloride sah (3), a key
intermediate in the production of trandolaprilat and trandolapril. This step final step is known
within the art, and generally comprises treatment with esterification agents including, but not
limited to, thionyl chloride, benzyl alcohol, and dichloromethane, as disclosed in U.S. Patent No.
4,879,392. Although the conversion of compound (5) to compound (3) is disclosed, the
processes for the production of compound (5), as detailed herein are novel and convey
significant improvements over the prior art.
Alternatively, it is also possible to convert the hydrochloride salt of (2S,3aR,7aS)-Ethyl
l-((S)-l-phenylethyl)octahydro-lH-indole-2-carboxylate (16) directly into (25',3ai?,7a5)-benzyl
octahydro-l//-indole-2-carboxylate hydrochloride salt (3) without converting compound (16) to
-16-
compound (5). This process involves the reaction of compound (16) with benzyl alcohol m the
presence of heat, and the removal of ethanol.
The cumulative process described in the two previous embodiments for the production of
(2S,3aR,7aS)-octahydro-lH-iridole-2-carboxylic acid (5) from ethyl 2-oxocyclohexane
carboxylate (6) provides multiple advantages over the prior act methods. Primarily, the
embodiments provide a nine-step process for the production of compovmd (5), which is useful in
the production of clinically significant compounds, such as trandolapril, described previously.
The reduction in the nvimber of steps provides significant benefits with regard to the efficiencies
of production, as well as improving the cost-effectiveness of the production. Additionally, the
process requires less solvent compared to previous methods, thereby providing additional cost
benefits.
4. Alternative Process for Generating (25,3aif,7a5)-octahydro-ljy-indole-2-carboxylic acid
(5) Using the Hoffman Reaction
Additionally, as depicted in Figure 3, the production of (25',3a/?,7aiS)-benzyl octahydrol/
ir-indole-2-carboxylate hydrochloride salt (3), a key intermediate in the production of
trandolaprilat and trandolapril, may be produced using a starting material of crystalline ((15,25)-
2-((iS)-l-phenylethylamino) cyclohexyl)methanol (11). The first step of the process involves
reaction with a catalyst including, but not limited to, palladium on carbon or palladium
hydroxide on carbon in the presence of an alcohol such as methanol to produce {(lS,2S)-2-
aminocyclohexyl)methanol (17). The remaining steps in the conversion of compound (17) to the
hydrochloride salt, and eventual conversion to (25,3a/?,7aiS)-benzyl octahydro-l^-indole-2-
carboxylate hydrochloride salt (3) are based upon the teachings of U.S. Patent No. 4,879,392,
which is fully incorporated herein by reference. Generally, the remaining steps can be described
as follows. Compound (17) is subjected to treatment with sodium cyanide in the presence of
formaldehyde to produce compovmd (18), as illustrated in Figure 3. Subsequently, compound
(18) is first reacted with trimethylsilyl chloride, and then the product of that reaction is treated
with benzyl methoxychloride to produce compound (19). Further, compound (19) is then
subjected to three sequential reactions to produce compound (20) as illustrated in Figure 3.
Specifically, compound (19) is first subjected to treatment with hydrochloric acid. Subsequently,
methanesulfonyl chloride is added to the reaction mixture. Thereafter, potassium hydroxide is
added to the reaction to produce compound (20). After compound (20) is produced, the
-17-
compound is treated with aqueous mineral acid to produce the hydrochloride salt of compound
(5), as disclosed previously. As described previously, compound (5) may then be treated with
thionyl chloride, benzyl alcohol, and dichloromethane to produce (25',3ai?,7aS)-benzyl
octahydro-l//-indole-2-carboxylate hydrochloride salt (3).
5, The Current Embodiments Compared to Previous Methods
Figure 6 illustrates the differences between the embodiments discussed herein and other
embodiments. The ultimate goal of the current invention is to produce (25',3ai?,7aS)-benzyl
octahydro-l/f-indole-2-carboxylate hydrochloride salt (3), which is a key intermediate
compound in the production of trandolaprilat and trandolapril. According to previous methods,
the production of compound (3) requires a process that entails twenty-two steps and a cycle time
of 11-12 weeks. The current invention reduces the number of steps in the process by the several
embodiments described herein. In one embodiment, imder the solvent approach, the current
invention describes a four-step process to produce compound (11) from a starting material of
ethyl 2-oxocyclohexane carboxylate (6) (a keto-ester) as shown in Figure 6. The production of
compound (11) can then be followed by a five step process to produce compound (5), and the
one-step conversion of compound (5) to compound (3), which was previously disclosed in the
art. Thus, under the solvent approach, a keto-ester can be converted into compound (3) in ten
steps, as opposed to the twenty-two steps described in the prior art. Furthermore, the cycle time
for the solvent approach is only 3-4 weeks. In addition, the solvent approach does not require a
catalyst and requires less solvent than other methods, leading to a more efficient and costeffective
alternative with a significantly decreased cycle time.
In another embodiment, similarly incorporating the solvent approach, as illustrated in
Figure 6, compound (11) can be produced in four steps, and compound (16) may be produced in
an additional four steps. However, in this embodiment compound (16) may be directly
converted into compound (3), without the conversion to compound (5). In this embodiment, the
conversion from the keto-ester to compound (3) includes a total of nine steps, as opposed to
twenty-two steps, with all of the benefits previously described. Therefore, this embodiment
provides numerous advantages compared to previous methods.
-18-
In a further embodiment, illustrated in Figure 6, ethyl 2-oxocycIohexane carboxylate (6)
may be converted to compound (11) by means of the catalyst approach, as described herein,
which also requires a four-step process. In this embodiment, the production of compound (11)
can then be followed by a five step process to produce compound (5), and the one-step
conversion of compound (5) to compound (3), which was previously disclosed in the art. Thus,
under the solvent approach, a keto-ester can be converted into compound (3) in ten steps, as
opposed to the twenty-two steps described in the prior art. Thus, the method of this embodiment
requires significantly fewer steps, leading to a more efficient and cost-effective alternative.
In yet another embodiment, illustrated in Figure 6, ethyl 2-oxocyclohexane carboxylate
(6) may be converted to compound (11) by means of the catalyst approach, as described herein,
which also requires a four-step process. Similar to the previous embodiments, compound (16)
may be produced in an additional four steps. However, in this embodiment compound (16) may
be du-ectly converted into compoimd (3), without the conversion to compound (5). In this
embodiment, the conversion fi:om the keto-ester to compound (3) includes a total of nine steps,
as opposed to twenty-two, with all of the benefits previously described. Therefore, this
embodiment provides numerous advantages including fewer steps, leading to a more efficient
and cost-effective alternative.
In an additional embodiment, illustrated in Figure 6, compound (11) may be converted
into ((15,25)-2-aminocyclohexyl)methanol (17). Compound (17) can then be subsequently
converted into compound (5) by means of eight intermediate steps, as described in U.S. Patent
No. 4,879,392. As described previously, compound (5) can then undergo a one-step conversion
to produce (25',3ai?,7aS)-benzyl octahydro-li/-indole-2-carboxylate hydrochloride salt (3).
Therefore, the conversion of compound (11) to compound (3) requires 10 steps, rather than the
twenty-two steps described by the prior art process. Regardless of whether the solvent approach
or the catalyst approach is used to produce compound (11), both approaches require four steps to
convert the keto-ester starting material into compound (11). Therefore, under this embodiment,
to convert the keto-ester starting material [compound (6)] into compound (3) requires a total of
fourteen steps, compared to the twenty-two step process of other methods. Accordingly, this
embodiment requires fewer steps, leading to a more efficient and cost-effective process for
producing compound (3).
-19-
The compounds and processes of the invention will be better vmderstood by reference to
the following examples, which are intended as an illustration of and not a limitation upon the
scope of the invention. Each example illustrates at least one method of preparing various
intermediate compounds and further illustrates each intermediate utilized in the overall process.
These are certain preferred embodiments, which are not intended to limit the present invention's
scope. On the contrary, the present invention covers all alternatives, modifications, and
equivalents as can be included within the scope of the claims, routine experimentation, including
appropriate manipulation of the reaction conditions, reagents used, and sequence of the synthetic
route, protection of any chemical functionality that can be compatible with the reaction
conditions, and deprotection at suitable points in the reaction sequence of the method are
included within the scope of the present mvention.
Example 1
("6^-Ethvl 2-("l-phenvlethvlamino')cyclohex-l-enecarboxvlate (S)
^ ^ \ .C02Et
^ ^ NH
(8)
Ethyl 2-oxocyclohexane carboxylate (6, 484.9 g) and (>S)-(-)-l-phenylethylamine (7,
362.5 g) were charged into an RB flask followed by heptanes (1.5 L) and Ytterbium (III)
trifluromethane sulfonate (8.8 g). The contents were heated to reflux for 3 hours and the liberated
water was removed simultaneously and then cooled to 22° C (± 3 °C). The insoluble material
was filtered and the filtrate was concentrate on a rotary evaporator under vacuum to afford 869.4
g of (5)-ethyl 2-(l-phenylethylamino)cyclohex-l-enecarboxylate (8) as an oil.
^ Example 2
(lR.2SVEthvl 2-('rSVl -phenvlethvlamino'lcvclohexanecarboxvlate (9)
-20-
H
^ ^ 1 NH
HjC*" ^ P h
(9, Major isomer)
Acetic acid (1.0 L) was added to a reactor followed by sodium borohydride (100 g) with
cooling between 16-30° C under nitrogen in NLT 1 hour and mixed for NLT 30 minutes.
Acetonitrile (500 mL) was added and mixed for NLT 30 minutes, and the cooled to below 5° C.
A solution of (5)-ethyl 2-(l-phenylethylamino) cyclohex-1-enecarboxylate (8, 269 g) dissolved
in acetonitrile (250 mL) was added in NLT 30 minutes, while maintaining the temperature
between 2-8° C and then the reaction mixture was warmed to 22° C, and mixed for NLT 4 hours.
The mixture was cooled below 5° C and quenched with 1.77 L of 25% aqueous sodiimi
hydroxide solution, water (1.3 L) and heptanes (0.75 L) and the pH was adjusted pH to -8.0.
The organic layer was separated and the aqueous layer was extracted with heptanes (2 x 0.75 L),
and then the combined heptane layers were washed with water (2 x 0.75 L) and 3.5 M aqueous
sodium chloride solution (0.75 L). The heptane solution was then dried using anhydrous
magnesium sulfate and concentrated under vacuum to afford 243.9 g of (li?,25)-Ethyl 2-((5)-lphenylethylamino)
cyclohexanecarboxylate (9) as the major isomer.
Example 3
(15',25)-Ethyl 2-(('5^-l-phenvlethvl amino)cvclohexanecarboxvlate (10)
H
^ ^ H NH
H,C-*" ^ P h
(10, Major isomer)
-21-
Tetrahydrofiiran (1.25 L) was charged to a reactor followed by ^butanol (150 mL), and
sodium /-butoxide (313 g) under nitrogen at ambient temperature. Additional tetrahydrofiiran
(1.0 L) was added and then the contents were cooled to <10° C. A solution of (li?,25)-ethyl 2-
((5)-l-phenylethylamino)cyclohexane carboxylate (9, 243.9 g) in tetrahydrofiiran (300 mL) was
added in NLT 30 minutes, while maintaining the temperature between 6-12° C. After the
addition was complete, the mixture was warmed to 22° C in NLT 30 minutes and fiirther mixed
for NLT 4 hours under nitrogen. The contents were cooled to <10° C and the reaction was
quenched with a solution of ammonium chloride (269.3 g) and water ui NLT 30 minutes, while
maintaining the temperature between 6-12° C. The lower aqueous layer was separated and
extracted with 750 mL of heptanes. The upper organic layer was concentrated to about 0.8 L
volume and extracted with the heptanes solution. The aqueous layer was separated and extracted
with fi-esh heptanes (2 x 0.75 L) and the combined organic layers were washed with water (2 x
0.75 L) and 3.5 M aqueous sodium chloride solution (0.75 L), and dried with anhydrous
magnesium sulfate. Concentration of the organic layer under vacuum gave 237.9 g of (IS,2S)-
ethyl 2-((5)-l-phenylethyl aniino)cyclohexane carboxylate (10) as a major isomer.
Example 4
ri5,25^-2-rr6^-l-Phenvlethvl aminolcvclohexv^methanol ri2')
H
•^ ^ - OH
H,C»"' ^ P h
(11, Major isomer)
Tetrahydrofuran (1.9 L) was charged to a reactor and cooled to 15° C and lithium
borohydride (52.8 g) was added under nitrogen. A solution of (15',25)-Ethyl 2-((5)-lphenylethylamino)
cyclohexanecarboxylate (10, 237.9 g) in tetrahydrofioran (0.35 L) was added
and the reaction mixture was heated to reflux for NLT 12 hours, under nitrogen. The mixture
-22-
was cooled to below 10° C and acetic acid (NLT 278 mL) was added, while maintaining the
temperature between 5-15° C in NLT 30 minutes. 25% aqueous sodium hydroxide solution
(1.78 L) and water (~2 L) were added to adjust pH to -8.7. The aqueous layer was separated and
extracted with 2 x 0.75 L of heptanes, which was kept aside. The organic layer was concentrated
to about 0.8 L volume and combmed with the heptane extracts and additional water (0.75 L).
The aqueous layer was separated and extracted with heptanes (0.75 L) and the combined organic
extracts were washed with water (2 x 0.75 L), 3.5 M aqueous sodium chloride solution (0.75 L)
and dried using anhydrous magnesium sulfate. The filtered solution was concentrated under
vacuirai and provided 184.1 g) of (15',25)-2-[(5)-l-phenylethyl amino]cyclohexyl)methanol (11)
as the major isomer.
Example 5
Ethvl 2-((( 15'.25^-2-aivdroxvmethvl)cvclohexviyr.S^-1 -phenvlethyHamino^acetate (12)
H
^ ^ - OH
— £ N COjEt
H,C*""^Ph
(13, Major isomer)
A solution of (15,25)-2-[(5)-l-phenylethyl amino]cyclohexyl)methanol (11) (339.1 g)
dissolved in acetonitrile (2.2 L) was charged to a reactor followed by ethyl bromoacetate (12)
(234.2 mL) and anhydrous sodium carbonate (224.2 g) under nitrogen. The contents were heated
to reflux temperature for NLT 18 hours with vigorous agitation. Acetonitrile was distilled under
vacuum to about 1 L volume, cooled to <30 °C and diluted with 0.75 L of heptanes and 1.0 L of
water. The aqueous layer was separated and extracted with heptanes (2 x 0.75 L), and the
combined organic layers were washed with water (0.75 L) followed by 0.75L 3.5 M aqueous
sodium chloride solution. The heptane layer was dried with anhydrous magnesium sulfate and
-23-
concentrated under vacuum to afford 557.8 g of ethyl 2-{((lS,2S)-2-
(hydroxyniethyl)cyclohexyl)((5)-l-phenylethyl)amino) acetate (13) as the major isomer.
Example 6
Ethvl 2-('('ri6'.25)-2-((methvlsulfonvloxv)methvncvclohexviyr5)-1 -phenvlethvnamino) acetate
04}
H
•^ ^•" ^OS02CH3
^ ^ 5 ^ N COoEt
H , C * " " ^ Ph
(14, Major isomer)
Dichloromethane (225 ml) was charged to a 1 L flask containing ethyl 2-(((lS,2S)-2-
(hydroxymethyl)cyclohexyl)((5)-l-phenylethyl)amino)acetate (13) (22.4g) and triethylamine
(37.1 mL) was added and the entire solution was cooled to 5 °C under nitrogen.
Methanesulfonyl chloride (15.5 mL) was added in NLT 10 minutes and the mixture was stirred
for NLT 15 minutes at low temperature (between 2-10° C). The reaction mixture was then
warmed to 22° C and stirred for NLT 1 hour and then quenched with 110 mL of ice-water while
the stirring was continued for NLT 30 minutes. The lower organic layer was separated and the
upper aqueous layer was extracted with 110 mL of dichloromethane. The combined organic
layers were washed with water (2 x HO mL), dried with anhydrous sodium sulfate and
concentrated under vacuum to afford 30.1 g of ethyl 2-{({lS,2S)-2-
((methylsulfonyloxy)methyl)cyclohexyl) ((5)-l-phenylethyl)amino) acetate (14, major isomer)
as a viscous oil.
• Example 7
(25.3ai?.7a5)-Ethvl l-('(5)-l-phenvlethvDoctahvdro-l//-indole-2-carboxvlate CIS)
-24-
H
\ ^C02Et
* X
(15)
Tetrahydrofuran (210 mL) was charged to 1 L flask containing ethyl 2-(((liS',25)-2-
((methylsulfonyIoxy)methyl)cyclohexyl)((5)-l-phenylethyl)aniino)acetate (14, 30.1 g), sodium tbutoxide
(9.6 g) was added at ambient temperature between 19-24° C xmder nitrogen. The
mixture was then heated to 65° C and stirred for NLT 1 hour and cooled to 5° C. It was then
quenched with a solution of ammonium chloride (10.69 g) in water (34 mL) and concentrated to
about 100 mL volume. The mixture was diluted with heptanes (210 mL) and water (105 mL)
and the aqueous layer is further extracted with heptanes (2 x 105 mL). The combined organic
layers were washed with water (105 mL), followed by 3.5 M aqueous sodium chloride solution
(105 mL). The heptane layer was dried with anhydrous sodium sulfate and concentrated under
vacuum to afford 20.65 g of crude compound (15), which was purified on silica gel (700 g)
chromatography using 3-4% ethyl acetate in hexanes to afford 8.24 g of (25',3ai?,7aS)-ethyl 1-
((5)-l-phenylethyl) octahydro-l/f-indole-2-carboxylate (15) as a viscous oil.
Example 8
(25'.3aJ?.7a$^-Ethvl octahvdro-l//-indole-2-carboxvlate ri6)
H
a H
H
(16)
-25-
5% palladium on carbon (0.27 g) was added to a solution of (25,3a/?,7aS)-ethyl l-((5)-lphenylethyl)
octahydro-li7-indole-2-carboxylate (15) (2.7 g) in ethanol (20 mL) and the mixture
was heated at 60° C under hydrogen (14.5 psi) atmosphere for NLT 3 hours. The catalyst was
filtered and washed with fresh ethanol (15 mL). The combined filtrate was concentrated imder
vacuimi to afford 1.93 g of (25',3a/?,7aS)-Ethyl octahydro-l//-indole-2-carboxylate (16) as a
viscous oil.
Example 9
('25'.3aJg.7ai$^-Octahydro-l.^-indole-2-carboxvlic acid hydrochloride (5)
H
S HHCI
(5)
6 N hydrochloric acid (6 mL) was added to 0.42 g of (25',3ai?,7aiS)-ethyl octahydro-1/findole-
2-carboxylate (16) and heated to reflux for NLT 4 hours. The mixture was concentrated
and dried under vacuum to afford 0.42 g of (25',3ai?,7aiS)-octahydro-l//-Lndole-2-carboxylic acid
hydrochloride (5) as a crystalline solid.
Example 10
(5^-Ethvl 2-(l-phenvlethvlamino)cyclohex-l-enecarboxvlate (8)
(8)
-26-
Ethyl 2-oxocyclohexane carboxylate (6, 170.2 g, 1.0 mol, 1.0 equiv.) and (5)-(-)-lphenylethylamine
(7,126.0 g, 1.04 mol, 1.04 equiv., ee: >99%) were sequentially charged into a
1-L reaction flask fitted with a Dean-Stark trap, condenser and heating mantle with temperature
controller probe containing toluene (500 mL). The solution was heated to reflux with agitation at
100-120 °C for NLT 3 h to azeotropically remove the theoretical amount of water (-18 mL, 1.0
mol). The reaction mixture was then cooled to 22 ± 3 °C temperature. Resulting clear pale
yellow solution containing the theoretical amount of (5)-ethyl 2-(l-phenylethylamino)cyclohex-
1-enecarboxylate (8, 273.4 g, 1.0 mol) was used in the next step without purification or
concentration. GC (Column: DB-5, Size: 0.53 mm x 30 m): Temperature Gradient: 20 to 200 °C
in 20 min and hold at 200 °C in 10 min. Injection temperature: 180 °C, FID detector temperature:
280 °C, R,: 20.2 min, >99% (PA).
Example 11
('li?.25^-Ethvl 2-(('5^-l-phenvlethvlamino)cyclohexanecarboxvlate hydrobromide (9)
H
^ ^ E NH HBr
(9)
Isobutyric acid (1.86 L, 1.762 Kg, 20.0 mol, 20.0 equiv.) was added to a 4 L reactor
under nitrogen and cooled to 2-5 °C temperature. Sodium borohydride (113.49 g, 3.0 mol, 3.0
mole equiv.) is added with agitation between 0-10 °C in NLT 2 h. The mixture warmed to 18 °C
temperature and mixed for an additional NLT 15 min. The solution was cooled to -5 °C to -8
°C then the toluene solution containing the (5)-ethyl 2-(l-phenylethylamino)cyclohex-lenecarboxylate
(8, 273.37 g, 1.0 mol, 1.0 equiv.) was added over 50 min while maintaining the
temperature at'O ± 2 °C. The contents were mixed for 2 h and 40 min and quenched by the slow
addition of 1 L of 4N hydrochloric acid while maintaining the temperature below 10 °C. To this
-27-
mixture, 2.1 L of 25 w/w% sodium hydroxide solution was added while maintaining the
temperature at 5 - 20 °C. The phases were allowed to settle and the upper layer organic was
separated. The lower aqueous layer was extracted with of toluene (2 x 680 mL). The combined
organic layers were washed sequentially with water (2 x 680 mL) and 3.5 M aqueous sodium
chloride solution (2 x 680 mL). The toluene solution was then dried using anhydrous
magnesium sulfate (30 g), filtered and concentrated under vacuum to afford 298.1 g of crude
(li?,25)-Ethyl 2-((5)-l-phenylethylamino) cyclohexanecarboxylate (9) free base, as an oil. The
crude product was dissolved in 1.1 L of ethyl acetate in a 2 L reactor flask and cooled to -0.5 °C
temperature. To this mixture, 247 mL of 30 wt. % hydrogen bromide in propionic acid was
added with agitation over I h and 20 min, while maintaining the temperature at 0 ± 2 °C. The
contents were stirred for an additional 1 h at 0 °C and the crystalline product was filtered and
washed twice with 300 mL of cold (0 °C) ethyl acetate. The wet cake was dried at 45 °C
temperature under vacuum for 5 h to afford 302.3 g of the desired (li?,25)-Ethyl 2-({S)-\-
phenylethylamino)cyclohexanecarboxylate hydrobromide salt (9). The dried hydrobromide salt
(9,) and 2.47 L of acetonitrile was added to a 3 L reactor flask under nitrogen then heated to
reflux at approximately 81-82 °C temperature. After the solids were dissolved, the clear solution
was gradually cooled to 0 °C over 3 h period and held for 30 min at 0 ± 2 °C temperature. The
solids were filtered and washed with 200 mL of cold (0 °C) acetonitrile. The wet cake was dried
at 40-45 °C temperature under vacuum for 18 h to afford 246.2 g of the purified (li?,25)-Ethyl 2-
((5)-l-phenylethylamino)cyclohexanecarboxylate hydrobromide salt in 69.1% yield, as a white
powder. Analytical HPLC (Daicel Chiralpack AD-RH column. Size: 150 x 4.6 mm); 0.02 M
Ammonium acetate buffer (pH: 7.7-7.8):Acetonitrile/50:50, 0.3 mL/min, Wave length: 220 nm.
Column oven temperature: 55 °C, R,: 16.14 min, 99.75 % (PA); 'H N M R (D2O, 400 MHz): 6
7.56 - 7.50 (m, 5 H), 4.62 (q, 1 H, J = 10.4, 6.8 Hz), 4.39 - 4.31 (m, 1 H), 4.30 - 4.22 (m, 1 H),
3.27 - 3.15 (m, 2 H), 2.26 - 2.19 (m, 1 H), 1.81 - 1.64 (m, 3 H), 1.70 (d, 3 H, J= 6.8 Hz), 1.57 -
1.39 (m, 2 H), 1.33 (t, 3 H , / = 7.2 Hz), 1.30 - 1.18 (2 H); LC-MS (m/z): 276.2 (M + H)^
Example 12
(15',251-Ethvl 2-(("6^-l-phenvlethvl amino)cvclohexanecarboxvlate hydrochloride (10)
-28-
H
(10)
(li?,25)-Ethyl 2-((5)-l-phenylethylaniino)cyclohexanecarboxylate hydrobromide (9, 130
g, 0.356 mol, 1.0 equiv.) was added to a 2-L reactor containing 529 mL of 10% w/v sodium
carbonate solution and 260 mL of heptanes at ambient temperature. The slurry was mixed
rapidly at 18-25 °C for NLT 30 min. During this period, the solids were dissolved to form clear
solution, which was allowed stand for NLT 10 min to for two clear layers. The phases were
separated and retained both layers. The lower aqueous layer was extracted twice with 260 mL of
heptanes. The heptanes extracts were combined and washed sequentially with 260 mL of tap
water then 260 mL of 3.5 M sodivim chloride solution. The heptanes extract was dried with
anhydrous magnesium sulfate (10.4 g), filtered and concentrated under vacuum to afford 98.2 g
of free base (9) as viscous oil. Anhydrous tetrahydrofuran (472 mL) was added to a 3-L
clean/dry reactor, which was equipped with a mechanical stirrer, temperature probe under
nitrogen. r-Butanol (70.2 mL) was added followed by sodium r-butoxide (70.2 g, 0.731 mol,
2.05 equiv.) carefully in portions under nitrogen atmosphere with cooling, while maintaining the
temperature below 25 °C. An additional 472 mL of anhydrous tetrahydrofuran was added as a
rinse and then the contents were cooled to: 6-12 °C. The (li?,25)-ethyl 2-((5)-lphenylethylamino)
cyclohexane carboxylate (9) free base, which was prepared above was
dissolved in 95 mL of anhydrous tetrahydrofuran and the solution was added via addition furmel
to the sodium /-butoxide slurry while maintaining the temperature at 6-12 °C temperature under
nitrogen over a period of approximately 45 min. After the addition was complete, the mixture
was stirred for an additional 15 min at 6-12 °C temperature then the resulting pale yellow/offwhite
slurry was warmed to 19-25 °C and mixed for NLT 4 h under nitrogen. The contents were
cooled to 6-12 °C and quenched using an 18 wt.% aqueous ammonium chloride solution (58.5 g
ammonium chloride in 322 mL of water) while maintaining the temperature at 5-15 °C. After
mixing the contents for an additional 30 min at 20-25 °C temperature the layers were separated.
-29-
The upper organic layer was separated and concentrated under vacuum at an internal temperature
NMT 50 °C to an approximately 1/3 to 1/4 final volume. The bottom aqueous lower layer in 3 L
reaction flask was extracted with 3 x 259 mL of heptanes. The two heptanes extracts and the
separately concentrated upper organic layer were combined and washed sequentially with 2 x
259 mL of water and 2 x 259 mL of 3.5 M aqueous sodium chloride solution. The heptanes
solution was dried using anhydrous magnesium sulfate (10.4 g), filtered and concentrated on a
rotary evaporator under vacuum at NMT 70 °C temperature. Residual solvents in the resulting
crude product were removed using a high vacuum pump to afford 93 g of crude (15,25)-ethyl 2-
((iS)-l-phenylethylamino)cyclohexanecarboxylate (10) as pale yellow viscous oil. The crude
(15',25)-ethyl 2-((5)-l-phenylethyl amino)cycIohexanecarboxylate (10) was dissolved in 332 mL
of ethanol (2B, 200 proof) in a 1-L clean/dry reactor flask equipped with a mechanical stirrer,
temperature probe under nitrogen with mixing. From a dropping funnel charge 117 mL of a
solution of 14 wt.% hydrogen chloride in ethanol was added to the reactor over 5-10 min at
NMT 40 °C temperature. The mixture was stirred for 30 min at less than 40 °C as a white solid
precipitates. The mixture was heated to 65-75 °C to dissolve the solids and the contents were
cooled slowly at approximately at rate of 10-15 °C per h to 0-5 °C temperature and held for 4 h.
The white solid was collected via filtration and washed with 100 mL of cold (0 °C) ethanol (2B,
200 proof). The solid was dried in a vacuum oven at 45-50 °C temperature to afford 64.9 g of
(\S,2S)-ethyl 2-((5)-l-phenylethylamino)cyclohexane carboxylate hydrochloride (10) in 58.5%
as a white solid. Analytical HPLC (Daicel Chiralpack AD-RH column, Size: 150 x 4.6 mm);
0.02 M Ammonium acetate buffer (pH: 7.7-7.8):Acetonitrile/50:50, 0.3 mL/min, Wave length:
220 nm. Column oven temperature: 55 °C, R,: 16.00 min, 98.98 % (PA); 'H NMR (D2O, 400
MHz): 6 7.51 - 7.46 (m, 5 H), 4.56 (q, 1 H, / = 13.9, 7.0 Hz), 4.27 - 4.14 (m, 2 H), 3.47 (dt, 1 H,
J = 11.4, 3.9 Hz), 2.58 (dt, 1 H, J = 11.6, 4.0 Hz), 2.17 - 2.10 (m, 1 H), 1.91 - 1.84 (m, 1 H),
1.75 - 1.62 (m, 3 H), 1.68 (d, 2 H, 7 = 6.8 Hz), 1.48 - 1.34 (m, 2 H), 1.27 (t, 3 H, J = 7.2 Hz),
1.25 - 1.15 (m, 2 H); LC-MS (m/z): 276.2 (M + H)^.
-30-
Example 13
(16'.25^-Ethvl 2-('r5)-l-phenvlethyl amino )cvclohexanecarboxvlate hydrochloride ("10^ via the
recycling method
H
^ ^ - ' H ^ N H H C l
(10)
Mother liquor containing the hydrochloride salt of (Ii?,25)-Ethyl 2-((5)-lphenylethylamino)
cyclohexane carboxylate (9) was concentrated and added to a 2-L reactor
containing 493 mL of 10% w/y sodium carbonate solution and 216 mL of heptanes at ambient
temperature. The slurry was mixed rapidly at 18-25 °C for NLT 30 min. During this period, the
solids were dissolved to form clear solution, which was allowed stand for NLT 10 min to for two
clear layers. The phases were separated and retained both layers. The lower aqueous layer was
extracted twice with 216 mL of heptanes. The heptanes extracts were combined and washed
sequentially with 216 mL of tap water then 216 mL of 3.5 M sodium chloride solution. The
heptanes extract was dried with anhydrous magnesium sulfate (8.6 g), filtered and concentrated
under vacuum to afford 56.8 g of free base (9, 0.206 mol, 1.0 equiv.) as viscous oil. Anhydrous
tetrahydrofiiran (260 mL) was added to a 2-L clean/dry reactor, which was equipped wdth a
mechanical stirrer, temperature probe under nitrogen. ^Butanol (40.0 mL) was added followed
by sodium ^butoxide (40.0 g, 0.416 mol, 2.02 equiv.) carefully in portions under nitrogen
atmosphere wdth cooling, while maintaining the temperature below 25 °C. An additional 269
mL of anhydrous tetrahydrofiiran was added as a rinse and then the contents were cooled to: 6-
12 °C. The (l^,25)-ethyl 2-((5)-l-phenylethylamino) cyclohexane carboxylate (9) free base, -
which was prepared above was dissolved in 54 mL of anhydrous tetrahydrofiiran and the solution
was added via addition flmnel to the sodium /-butoxide slurry while maintaining the temperature
at 6-12 °C teirjperature under nitrogen over a period of approximately 45 min. After the addition
was complete, the mixture was stirred for an additional 15 min at 6-12 °C temperature then the
-31-
resulting pale yellow/off-white slurry was warmed to 19-25 °C and mixed for NLT 4 h under
nitrogen. The contents were cooled to 6-12 °C and quenched using an 18 wt.% aqueous
ammonium chloride solution (33.3 g ammonium chloride in 184 mL of water) while maintaining
the temperature at 5-15 °C. After mixing the contents for an additional 30 min at 20-25 °C
temperature the layers were separated. The upper organic layer was separated and concentrated
under vacuum at an internal temperature NMT 50 °C to an approximately 1/3 to 1/4 final
volume. The bottom aqueous lower layer in 3 L reaction flask was extracted with 3 x 148 mL of
heptanes. The two heptanes extracts and the separately concentrated upper organic layer were
combined and washed sequentially with 2 x 148 mL of water and 2 x 148 mL of 3.5 M aqueous
sodium chloride solution. The heptanes solution was dried using anhydrous magnesium sulfate
(5.9 g), filtered and concentrated on a rotary evaporator under vacuum at NMT 70 °C
temperature. Residual solvents in the resulting crude product were removed using a high
vacuum pump to afford 53.7 g of crude (lS,2S)-ethy\ 2-((S)-lphenylethylamino)
cyclohexanecarboxylate (10) as pale yellow viscous oil. The crude (15,25)-
ethyl 2-((5)-l-phenylethylamino) cyclohexanecarboxylate (10) was dissolved in 192 mL of
ethanol (2B, 200 proof) in a 1-L clean/dry reactor flask equipped with a mechanical stirrer,
temperature probe under nitrogen with mixing. From a dropping fiinnel charge 68 mL of a
solution of 14 wt.% hydrogen chloride in ethanol was added to the reactor over 5-10 min at
NMT 40 °C temperature. The mixture was stirred for 30 min at less than 40 °C as a white solid
precipitates. The mixture was heated to 65-75 °C to dissolve the solids and the contents were
cooled slowly at approximately at rate of 10-15 °C per h to 0-5 °C temperature and held for 4 h.
The white solid was collected via filtration and washed with 58 mL of cold (0 °C) ethanol (2B,
200 proof). The solid was dried in a vacuum oven at 45-50 °C temperature to afford 32 g of
(lS,2S)-ethyl 2-((5)-l-phenylethylamino)cyclohexane carboxylate hydrochloride (10) in 49.8%
as a white solid. Analytical HPLC (Daicel Chiralpack AD-RH column, Size: 150 x 4.6 mm);
0.02 M Ammonium acetate buffer (pH: 7.7-7.8):Acetonitrile/50:50, 0.3 mL/min, Wave length:
220 nm. Column oven temperature: 55 °C, R^ 16.01 min, 98.63 % (PA).
-32-
Example 14
('15'.25^-2-rr5^-l-Phenvlethvl aminolcvclohexvnmethanol r i l)
H
^ N- OH
(11)
Charge {lS,2S)-Qthyl 2-((5)-l-phenylethylamino)cyclohexane carboxylate hydrochloride
(10, 163.5 g, 0.524 mol, 1.0 equiv.) to a 2-L reactor containing 788 mL of 10% w/v sodium
carbonate solution and 327 mL of heptanes at ambient temperature. Mix the contents rapidly at
18-25 °C for NLT 30 min. During this period, the solids were dissolved and agitation was
stopped for NLT 10 min to form two clear layers. Separate the phases and retain both layers.
Extract the lower aqueous layer twice with 327 mL of heptanes each. Combine all heptanes
extracts and wash sequentially with 327 mL of tap water then 327 mL of 3.5 M aqueous sodium
chloride solution. Dry the heptanes solution with anhydrous magnesium sulfate (13.5 g), filter
and concentrate under vacuum to yield 148.9 g of (15,25)-ethyl 2-((5)-l-phenylethyl
amino)cyclohexane carboxylate (>99% yield and contains residual heptanes) free base as an oil.
Charge 1154 mL of tetrahydrofuran to the free base in a clean/dry 4 L reactor flask under
nitrogen at ambient temperature, which is equipped wdth mechanical stirrer, thermocouple, and
begin agitation. At ambient temperature, charge potassium borohydride (42.4 g, 0.786 mol, 1.5
mol equiv.) followed by lithium chloride (33.3 g, 0.785 mol, 1.5 mol equiv.) under nitrogen. The
reaction mixture was heated to reflux (67 °C) with agitation and continue for NLT 12 h under
nitrogen atmosphere. The mixture was cooled to below 22 °C temperature and charged 1734 mL
of tap water over 20 min period using an addition fiinnel, while maintaining the temperature at
NMT 27 °C. The contents were mixed for an additional 30 min at ambient temperature and
allowed the layers to separate. The upper organic layer was separated and concentrated using a
rotary evaporator at NMT 50 °C temperature to yield crude product (11), as viscous oil. The
lower aqueous layer was extracted three times with 327 mL of heptanes each. Combined the
-33-
heptanes extracts were mixed with the concentrated viscous oil and wash the combined heptanes
solution was sequentially washed with 327 mL of water and 327 mL of 3.5 M aqueous sodium
chloride solution. The heptanes solution was dried with anhydrous magnesium sulfate (13.5 g),
filtered and concentrated using vacuum at a temperature NMT 70 °C. The resuhing crude
product was further dried using a high vacuum pump (-0.2 mmHg) for NLT 12 h period to
afforded 120.9 g of (15,25)-2-[(5)-l-Phenylethylammo]cyclohexyl) methanol (11) as a viscous
oil, which was carried to the next step without further purification. Analytical HPLC (Daicel
Chiralpack AD-RH column. Size: 150 x 4.6 mm); 0.02 M Ammonium acetate buffer (pH: 7.7-
7.8):Acetonitrile/50:50, 0.3 mL/min, Wave length; 220 nm. Column oven temperature: 55 °C, R^:
18.39 min, 98.66 % (PA); LC-MS (m/z): 234.2 (M + H)^.
Example 15
Ethyl 2-((( 15'.25^-2-nivdroxvmethvncvclohexvn((5^-1 -phenvlethvDamino^acetate ri3)
H
f ^- OH
^ ^ i ^ N COzEt
(13)
A solution of (15',25)-2-[(5)-l-phenylethylamino]cyclohexyl)methanol (11, 120.9 g,
0.524 mol, 1.0 equiv. based on HCl salt 10) dissolved in acetonitrile (610 mL) was charged to a 2
L reactor, which is equipped with mechanical stirrer and thermocouple under nitrogen
atmosphere. To this solution, ethyl bromoacetate (12, 104.9 g, 0.628 mol, 1.2 equiv.) and
anhydrous sodium bicarbonate (57.2 g, 0.681 mol, 1.3 equiv.) were added sequentially with
agitation. The contents were heated to reflux temperature for NLT 18 h with vigorous agitation
imder nitrogen atmosphere. Acetonitrile was distilled out under vacuum to about 300 mL
volume and the mixture was cooled to less than 30 °C temperature and diluted with 327 mL of
heptanes and 423 mL of water. The contents were mixed for NLT 15 min and allowed settle to
-34-
form two layers. The bottom aqueous layer was separated and further extracted with 2 x 327 mL
of heptanes. The two heptanes extracts were combined with the organic layer in the reactor and
washed sequentially with 1 x 327 mL of water and 1 x 327 mL 3.5 M aqueous sodium chloride
solution. The heptanes solution was dried using anhydrous magnesium sulfate (13.5 g), filtered
and concentrated under vacutmi at NMT 60 °C temperature. The crude product was further dried
under vacuum to afford 171.4 g of ethyl 2-(((15',25)-2-(hydroxymethyl) cyclohexyl)((5)-lphenylethyl)
amino) acetate (13) as viscous oil, which was carried to the next step without further
purification. Analytical HPLC (Daicel Chiralpack AD-RH column, Size: 150 x 4.6 mm); 0.02
M Anmionium acetate buffer (pH: 7.7-7.8):Acetonitrile/50:50, 0.3 mL/min, Wave length: 220
nm. Column oven temperature: 55 °C, R,: 23.62 min; LC-MS (m/z): 320.2 (M + H)"".
Example 16
Ethvl 2-((( 16'.2y)-2-((methvlsulfonvloxv)methvl)cvclohexvl)((5^-1 -phenvlethyl) amino)acetate
£14}
H
^ ^ • OSO2CH3
^ ^ H N COjEt
(14)
A solution of 167.4 g of ethyl 2-(((15,25)-2-(hydroxymethyl) cyclohexyl)((5)-lphenylethyl)
a'mino)acetate (13, 0.524 mol, 1.0 equiv. based on HCl salt 10) dissolved in 685 mL
of dichloromethane was added to a 2 L reactor, which is equipped with mechanical stirrer and
thermocouple under nitrogen atmosphere. To this solution, 63.8 g of triethylamine (0.629 mol,
1.2 equiv.) was added and the mixture was cooled to less than 5 °C temperature. 66 g (0.576
mol, 1.1 equiv.) of methanesulfonyl chloride was added dropwise while maintaining the
temperature below 10 °C and after the addition was complete, the mixture was stirred for an
additional 30 min and then warmed to approximately 20 °C temperature under nitrogen
-35-
atmosphere. The reaction mixture was stirred for NLT 1 h and quenched with 261 mL of icewater
at below 25 °C temperature and mixed for NLT 15 min. The lower organic layer was
separated and the upper aqueous layer was extracted with 2 x 135 mL of dichloromethane. The
combined organic layers were washed with 3 x 327 mL of water, dried using anhydrous
magnesium sulfate (13.5 g), filtered and concentrated on a rotary evaporator under vacuum at
NMT 60 °C temperature. The resulting crude product (viscous oil) was dried over night using a
high vacuum pump to afford 204.7 g of ethyl 2-(((15',25)-2-((methylsulfonyloxy)methyl)
cyclohexyl) ((iS)-l-phenylethyI)amino) acetate (14) as a viscous oil, which was carried to the
next step without fiirther purification. Analytical HPLC (Daicel Chiralpack AD-RH column.
Size: 150 x 4.6 nun); 0.02 M Ammonium acetate buffer (pH: 7.7-7.8):Acetonitrile/50:50, 0.3
mL/min, Wave length: 220 nm, Column oven temperature: 55 °C, R^ 17.23 min; LC-MS (w/z):
398.2 (M + H)^
Example 17
r25.3a/?.7a5^-Ethvl 1 -((S)-1 -phenvlethvDoctahvdro-l//-indole-2-carboxylate (15)
H
(15)
1.18 L of Anhydrous tetrahydrofuran was added to 2 L reactor, reactor, which is
equipped with mechanical stirrer and thermocouple under nitrogen atmosphere. With mixing,
60.4 g of sodium Nbutoxide (0.628 mol, 1.2 equiv.) was added and the mixture was cooled to
below 10 °C temperature. During this period, the solids were dissolved to form an slightly hazy
solution. To this mixture, a solution of 204.7 g of ethyl 2-(((15',2iS)-2-
((methylsulforiyloxy)methyl)cyclohexyl)((5)-l-phenylethyl)amino)acetate (14, 0.524 mol, 1.0
equiv. based on HCl salt 10) in 297 mL of anhydrous tetrahydrofuran was added over a period of
-36-
NLT 30 min, while maintaining the temperature below 10 °C. The reaction mixture was warmed
to 20 ± 3 °C and mixed for NLT 3 h under nitrogen atmosphere. The reaction was then
quenched using a solution of 50.3 g of ammonium chloride (0.942, 1.8 equiv.) in 267 mL of
water, slowly. The phases were allowed to separate and the upper tetrahydrofuran layer was
separated and concentrated on a rotary evaporator at NMT 50 temperature to an orange colored
product residue. The lower aqueous layer was extracted with 2 x 495 mL of heptanes. The
heptanes extracts were combined with the concentrated product residue and washed with 2 x 495
mL of 3.5 M aqueous sodium chloride solution. The heptanes extract was dried using anhydrous
magnesium sulfate (13.5 g), filtered and concentrated on a rotary evaporator at NMT 70 °C
temperature under vacuum. The resulting oil was further dried overnight under high vacuum to
afford 124.3 g of crude (25,3a/?,7aS)-ethyl l-((5)-l-phenylethyl)octahydro-l//-indole-2-
carboxylate (15) as a major isomer (de: >97%), which was carried to the next step without
further purification. Analytical HPLC (Daicel Chiralpack AD-RH column. Size: 150 x 4.6 mm);
0.02 M Ammonium acetate buffer (pH: 7.7-7.8):Acetonitrile/50:50, 0.3 mL/min, Wave length:
220 nm, Column oven temperature: 55 °C, R<: 28.59 min; LC-MS (m/z): 302.2 (M + Kf.
On a smaller batch size, the reaction crude product 15 was isolated by starting fi-om 30.14
g of crude ethyl 2-(((15',25)-2-((methyl sulfonyloxy)methyl)cyclohexyl)((5)-lphenylethyl)
aniino)acetate [14, which was prepared fi-om 15.0 g of ethyl 2-oxocyclohexane
carboxylate (6, 0.0882 mol)] was purified silica gel column chromatography using 2-5% Ethyl
acetate in hexanes. The combined product fraction pool was concentrated on a rotary evaporator
at NMT 60 °C to afford 8.24 g of (25,3a/2,7aS)-ethyl l-((5)-l-phenylethyl)octahydro-l//-indole-
2-carboxylate (15) was isolated as a major isomer (de: >97%). Analytical HPLC (Daicel
Chiralpack AD-RH column. Size: 150 x 4.6 mm); 0.02 M Ammonium acetate buffer (pH: 7.7-
7.8):Acetonitrile/50:50, 0.3 mL/min, Wave length: 220 nm, Column oven temperature: 55 °C, R,:
28.33 min, 98.13% (PA); 'H N M R (CDCI3, 400 Mz): 6 7.38 - 7.34 (m, 2 H), 7.27 - 7.22 (m, 2
H), 7.19 - 7.14 (m, 1 H), 4.01 (q, 1 H, J = 13.6, 6.8 Hz), 3.91 - 3.84 (m, 1 H), 5.83 - 3.76 (m, 1
H), 3.50 (dd, 1 H, / = 10.6, 2.0 Hz), 2.20 - 2.10 (m, 1 H), 1.84 - 1.77 (m, 2 H), 1.75 - 1.52 (m, 5
H), 1.34 (d, 3 H, J = 6.8 Hz), 1.24 - 0.96 (m, 4 H), 1.08 (t, 3 H, J = 7.1 Hz); ^^C NMR (CDCI3):
5 175.4, 143.9, 127.8, 127.5, 126.3, 67.9, 60.2, 59.4, 57.9, 43.7, 35.6, 32.0, 30.4, 26.0, 25.0, 15.6,
14.4; LC-MS (m/z): 302.2 (M + H)^.
-37-
Example 18
('25',3ai?.7aS)-Ethvl octahvdro-l//-indole-2-carboxvlate Hydrochloride ri6)
H
ft HHCl
(16)
127 g of Raney Nickel (WR Grace 2800, water slurry) was added to a solution of 127.2 g
of (25,3a/?,7aS)-ethyl l-((5)-l-phenylethyl)octahydro-l//-indole-2-carboxylate (15) in 400 mL
ethanol and the solution was mixed at room temperature in a Parr shaker apparatus for 30 min
under Argon. The catalyst was filtered off and washed with 400 mL of ethanol. To this pretreated
product solution was added 21.7 g of platinum hydroxide on carbon (Degussa, 50 wt. %
water). The mixture was hydrogenated for 1.5 h at 50 °C under 30 psig of hydrogen pressure.
The catalyst was filtered and washed with fi^esh ethanol (100 mL). The hydrogenated product
mixture was concentrated under vacuum at NMT 70°C. The resulting oil was added from a
dropping funnel over 10-20 min at a temperature range of 25-35 °C to a 500 mL flask containing
263 g of a 14 % ethanolic hydrogen chloride solution. The mixture was stirred for 1 h at ambient
temperature then concentrated on a rotary evaporator to remove solvent under vacuum at 50-60
°C. 400 mL of ethyl acetate was added to the residue and the mixture warmed to 35 °C. The
mixture was cooled to 22 °C over 30 min to form a precipitate. The slurry was cooled to 0-5 °C
and held for 2 h. The solids were collected and washed with 20 mL of 0-5 °C ethyl acetate. The
solids were vacuum dried in an oven at 45 °C to afford 34.0 g of (25',3ai?,7aS)-Ethyl octahydrol//-
indole-2-carboxylate hydrochloride salt (16). Analytical HPLC (Daicel Chiralpack AD-RH
column, Size: 150 x 4.6 mm); 0.02 M Ammonium acetate buffer (pH: 7.7-
7.8):Acetonitrile/50:50, 0.3 mL/min, Wave length: 220 nm. Column oven temperature: 55 °C, R,:
16,21 min, 97.95% (PA); 'H NMR (D2O, 400 MHz): 5 4.52 (dd, 1 H, 7= 11.2, 2.9 Hz), 4.30 (q,
2H,J= 14.2,J.16 Hz), 2.94 (dt, 1 H, J = 11.8, 3.6 Hz), 2.42 - 2.34 (m, 1 H), 2.22 - 2.15 (m, 1
-38-
H), 2.12-1.98 (m, 2 H), 1.95 - 1.87 (m, 1 H), 1.80-1.73 (m, 1 H), 1.72-1.52 (m, 2 H), 1.35 -
1.11 (m, 2 H), 1.30 (t, 3 H, J = 7.1 Hz); LC-MS (m/z): 198.2 (M+Hf.
Example 19
(25',3a/?.7a5^-Octahvdro-li/-indole-2-carboxvlic acid hydrochloride (5)
H
^ ^ ' '^X^CO^H
= HHCl
H
(5)
In a 500 mL reaction flask equipped with a distillation head was added 33.5 g (0.143 mol,
1.0 equiv.) of (25',3a/?,7a5)-Ethyl octahydro-li/-indole-2-carboxylate hydrochloride (16), 102 g
of water, and 102 g of cone, hydrochloric acid. The contents were heated to 94-96 °C
temperature with mixing for NLT 6 h while collecting about 9 mL of distillate at atmospheric
pressure. The reaction mixture was cooled to room temperature and concentrated to dryness on a
rotary evaporator. To the resulting crude product, 255 mL of acetonitrile was added and heated
for 1 h at reflux with mixing to break up and dissolve the solids. The mixture was cooled
gradually to 0-5 °C temperature at a rate of 10-15 °C per h, and held at 0-5 °C for NLT 2 h under
nitrogen atmosphere. The solids were collected via filtration and washed with 10-20 mL of
chilled (0-5 °C) acetonitrile. The product was dried at 45 °C under vacuum for 16 h to afford
25.6 g of (25,3a/?,7aS)-Octahydro-li/-indole-2-carboxylic acid hydrochloride (5) in 86.9% yield
as a white solid. ^H NMR (D2O, 400 MHz): 5 4.42 (dd, 1 H, J = 11.1, 2.7 Hz), 2.93, (dt, 1 H, J=
11.8, 3.6 Hz), 2.36 (ddd, 1 H, 7= 12.9, 6.7, 2.7 Hz), 2.31-2.16 (m, 1 H), 2.11-2.01 (m, 2 H),
1.92 - 1.90 (m, 1 H), 1.79 - 1.75 (m, 1 H), 1.68 - 1.53 (m, 2 H), 1.34 - 1.13 (m, 3 H); LC-MS
(m/z): 170.1 (M+H)"^. The isolated product (5) correlates to the material prepared according to
US487932 and Tetrahedron Lett., 1992, 33, 4889.
-39-
Further, (25',3ai?,7a5)-Octahydro-l//-indole-2-carboxylic acid hydrochloride (5, 25.0 g,
0.122 mol) is converted to the corresponding benzyl ester [(25',3a/?,7aS)-Benzyl octahydro-1//-
indole-2-carboxylate hydrochloride] using thionyl chloride, benzyl alcohol in dichloromethane in
90.1% yield (32.7 g) and the product was correlated by HPLC and NMR to the to the material
prepared according to US487932 and Tetrahedron Lett. 1992, 33, 4889. Analytical HPLC
(Daicel Chiralpack AD-RH column. Size: 150 x 4.6 mm); 0.02 M Ammoni\im acetate buffer
(pH: 7.7-7.8):Acetomtrile/50:50, 0.3 mL/min, 220 nm, Column chamber temperature: 55 °C, R^:
32.6 min, 99.34 % (PA); 'H NMR (D2O, 400 Nfflz): 5 7.49 - 7.43 (m, 5 H), 5.37 - 5.28 (q, 2 H,
J = 23.2, 12.0 Hz), 4.60 (dd, 1 H, / = 11.2,2.9 Hz), 2.95, (dt, 1 H, J = 11.8, 3.7 Hz), 2.36 (ddd, 1
H, J = 13.1, 6.9, 2.9 Hz), 2.25 - 2.15 (m, 1 H), 2.13 - 2.02 (m, 2 H), 2.03 - 1.96 (m, 1 H), 1.95 -
1.88 (m, 1 H), 1.65 - 1.53 (m, 2 H), 1.32 - 1.12 (m, 3 H); LC-MS (/w/z): 274.1 (M+H)".
Example 20
(ri5'.25)-2-Aminocvclohexvl)methanoU17)
H
(17)
5% Palladium on carbon (0.05 g) was added to a solution of (15,25)-2-[(5)-l-phenylethyl
amino]cyclohexyl)methanol (12, 0.5 g, 0.002 mol) dissolved in methanol (15 mL). The mixture
was heated at 60 ° C under hydrogen (14.5 psi) atmosphere for NLT 3 h. The mixture was
cooled to room temperature, flushed with nitrogen, the catalyst was filtered and washed with
fresh methanol (10 mL). The combined filtrate was concentrated vmder vacuum to afford 0.28 g
of ((liS',25)-2-aminocyclohexyl)methanol (17) in quantitative yield as a white solid. [a]^^D 9.1 (c,
0.0107 CHCI3), ^H NMR (CDCI3, 400 MHz): 5 3.61 - 3.54 (m, 2 H), 2.71 (bs, 3 H), 2.45 (dt, 1
H,J=10.6, 1.2Hz), 1.85-1.78 (m, 1 H), 1.74-1.65 (m, 1 H), 1.62-1.53 (m, 1 H), 1.40-1.30
-40-
(m, 1 H), 1.25 - 1.06 (m, 3 H), 0.91 - 0.80 (m, 1 H), '^C NMR (CDCI3): 6 70.2, 57.4,45.5,40.1,
28.6, 25.5, 25.5, For NMR of its enantiomer, ((li?,2i?)-2-AminocycIohexyl) methanol (17), see
reference J: ^;«. Chem Soc. 1996,118, 5502.

CLAIMS
1. A process for preparing (2S,3aR,7aS)-Octahydro- lH-indole-2-carboxylic acid
hydrochloride (5) comprising the steps of:
H H
r OH B r ^ COoEt f T OH
(12) ^ " CH3SO2CI
\ J>^ NaHC03, L ^ N ^ ^ ^ s . EtjN, "
^ ^ ^ ^ N H CH3CN ^ ^ £ N COjEt CH2CI2
H3C^^^'^' > h H3C^^^^^'^Ph
(11) (13)
H H
"^"2^"3 /-BuONa r X^COjEt 5o/„ pd/g
/ \ THF I JL / ""/pj H2,EtOH
^M ^ r n Ft ^^^£^N then
= y "^"^Et H I EtOH-HCl
H3C^^^""^Ph H3C^^^"'^Ph
(14) (15, Major isomer)
H H
[ ^ ^ ^ ' ' \ ^COjEt „p, ( ^ ^ - " ' ' ' ' X ^GOjH [5, (25,3a^,7a^-
V ; "'•-' » yZ^ Octahydro-l/f-
^ X^^ / '''w L ^A^tm / '''H indole-2-carboxylic
^ ^ S H C I ^^ SHCI acid H Q salt]
H H
(16)
-42-
2. The process of claim 1, wherein the process of making (1 S,2S)-2-[(S)-1 -
phenylethyl amino] cyclohexyI)methanoI (11) comprises the steps of:
NH2
I
(S)-(-)-7 Isobutyric acid
\ ^ ^ ' ' ^ ^ Toluene ^^ ^^^~^ Enamine (8)
O ^^ NH HBr-EtOAc
(6) (8)
H H H
r-BuONa KBH4, Ljq
\ ^>^ '-BuOH* L J^>^ THF *" \ /l>^
^ ^ I ^ NH HBr THF ^ - ^ | ^NH HCl ^^ I NH
H I HCl-EtOH Hi Hi
H3C^^^"""^Ph H3C^^^""^Ph H3e^^"'"^Ph
(9) (10) (11)
3. A process for preparing (2S,3aR,7aS)-Octahydro- lH-indole-2-carboxylic acid
hydrochloride (5) comprising the steps of:
-43-
H H
( ^ OH Br XOoEt r OH
(12) ^ ^ ^ " CH3SO2CI
\ ^ > w NajCOj, l\ J>^ ^ ^ ^ EtjN, *
^ ^ I ^ N H CH3CN ^ ^ I ^ N XOjEt CH2CI2
Yi,<^^ ^ P h H3C^^^" ^ P h
(11) (13)
^ ^ • • • " ' ' ^ O S 0 2 C H 3 ,.BuONa ^ \ ^^X^CO^Et 50,, p ^ ^
\ J>^ ^ \ THF L JL / "''H H2,EtOH
^ ~ ^ £ N COjEt ^^^T^N
H3e^"^"'^Ph H3C^^"^ ^ P h
(14)
(15, Major isomer)
H H
r ' ^ " ^ " " ' ' ' \ ^COjEt „p, r " ' ' ' ' ^ ••"'% ^C02H [5, (25,3a^,7aS)-
X; "'•^' * X; Octahydro-1/f-
\ ^Ui^ / '''\{ L J-,^ / '•'H indole-2-carboxylic
^ ^ ^ 1 N ^^1 HHCl acid HCl salt]
H H
(16)
-44-
4. The process of claim 1, wherein the process of making (lS,2S)-2-[(S)-lphenylethyl
amino] cyclohexyl)methanol (11) comprises the steps of:
NH,
I
(S)-(-)-7 , CH.CN ^
' \ ^ A ^ Yb(0Tf)2, \ ^ ^ ^ Enamine(8)
^ ^ 0 Heptane ^ NH
(6) (8)
H H ][
f-BuONa LiBH4^
\ ^>w /-BuOH* L J>^ THF \ ^C*^
^ ^ £ NH THF ^-^I^NH ^~^ g NH
H,C'"'"^Ph HjC* ^ P h HjC* ^ Ph
(9, Major isomer) (10, Major isomer) (11)
5. A process for preparing (2S,3aR,7aS)-Octahydro- lH-indole-2-carboxyIic acid
hydrochloride (5) comprising the steps of:
-45-
1 ^ 5%Pd/C,H2 I I NaCN^ I
^ ^ ^ ^ i ^ x j H MeOH \,./^=N,nLr HCHO* \ . ^ ^ / ^ H I H ij H
( " ) _ (17) (18)
H H
/ ^ , . ^ ^ ^ ^ ^ \ /Si(Me)3 ^ ^
l.TMS-g I I O 1 HCl I 2-PhCOCl - I 1 ZMeSO^a I 1 / ^ ^
^ ^ I ^ N ^CN 3.K0H ^ ^ ^ £ ^N
H J fi
(1^) (20, Mixture, a:P = 30:70)
H
Aq. Mineral Acid V^CO H
1 yHCI
(5) "
Dated this 16/01/2012