Field of Invention:
The invention relates to novel method for synthesis of optically pure (.SV-(-)-1,1'-
bi-2-naphthol and/or (R)-(+)-1,1'-bi-2-naphthol via resolution of racemic (RS)-1,1-bi-2-
naphthol through formation of co-crystal with optically active derivatives of γ -amino
acids.
Background of the Invention:
l.l'-bi-2-naphthol [CAS. No 602-09-05] [1] is one of the industrially important
chemicals and is produced in large quantities all over the world.

l,l'-bi-2-naphthol occurs in two optically active forms because of its restricted
rotation viz. (S)-(-)-1,1'-bi-2-naphthol (CAS No. 18531-99-2] and (R)-(+)-1,1'-bi-2-
naphthol [CAS No. 18531-94-7].
(S)-(-)-1,1-bi-2-naphthol and (R)-(+)-1,1'-bi-2-naphthol are generally obtained by
resolution of racemic i.e. (RS)-1,1'-bi-2-naphthol. which is synthesized by oxidative
coupling of 2-naphthol in presence of transition metal salts having variable valence such
as FcCl3. CuSO4. CuCT2. VO- complex, etc. (J. Org. Chem. 1989, 54, 1252)
Both the optically pure (S)-(-)-1,1'-bi-2-naphthol and (R)-(+)-1,1'-bi-2-naphthol
have wide applications in synthetic chemistry and are used as building blocks for the
synthesis/manufacture of many important chemicals including natural products.

(Tetrahedron 1995. 51, 9353; Tetrahedron 2000, 56, 2325); and also as chiral auxiliaries
in stoichiometric quantity as well as in catalytic amount in various asymmetric syntheses.
The optically pure (S)-1,1'-bi-2-naphthol and (R)-(+)-1,1'-bi-2-naphthol are
used as auxiliary or converted to specific chiral ligands for use in various asymmetric
reactions, such as, enantioselective reduction, in various catalytic asymmetric Diels-Alder
reactions, ene reactions, asymmetric Michael additions, alkylations, oxidations,
epoxidations and nitroaldol reactions etc.(Chem. Rev. 1998, 98, 2405-2494; Chem. Rev.
2007. 107. PR1-PR45).
Recently, it has also been demonstrated that optically active l.l'-bi-2-naphthol
can also be used for optical resolution of active pharmaceutical compounds such as
omeprazole, lamivudine etc. (OPRD, 2009, 13, 450-455) and as a chiral shift reagent for
the determination of the optical purity and absolute configuration of a wide range of
chiral compounds (Chirality. 2009).
The synthesis of enantiomerically pure (R) or (S)-1,1'-bi-2-naphthol has been
extensively studied with essentially two major approaches such as resolution (enzymatic
and chemical) and, asymmetric synthesis.
I) Enzymatic resolution:
Kazlaukas has reported cholesterol esterase catalyzed enantioselective hydrolysis
of binaphthol esters. The reported method requires an additional step for preparation of
binaphthol esters but unfortunately the said enzyme is not commercially available. (J.
Am. Chem. Soc, 1989, 111, 4953)
Rnantioselective trans-esterification reaction of rac-1-indanol with rac-1,1'-
binaphthyl-2-2-dibutyrate in presence of enzymes such as procine pancreatic lipase ,
procine pancreatin and cholesterol esterase have been reported. This method has been
demonstrated for mutual separation of rac-1 -indanol and racemic (RS) -1.1 '-bi-2-naphthol

but overall yield for optically pure l,l'-bi-2-naphthol is low and needs an additional step
for separation. Hence, this could not be an industrial process for obtaining optically pure
l.l'-bi-2-naphthol (Tetrahedron Lett. 1993, 34, 6057).
Enantioselective monomethyl etherification of racemic (RS)-1,1'-bi-2-naphthol in
presence of bovine serum albumin has demonstrated low enantiomeric excess. (J. Am.
Chem.Soc., 1996, 118.9990)
Lipase catalyzed resolution of (RS)-1,1'-bi-2-n.aphthol has also reported low
enantiomeric excess. The reported method needs an additional step for preparation of
binaphlhol esters. (Tetrahedron: Asymmetry 2003, 14. 289; Tetrahedron Lett. 2006, 47,
4797)
It is evident from the above that in enzymatic resolution methods, more often than
not, the separation is not economic and also enzymes are not available commercially.
Further, overall cost for obtaining optically pure 1,1'-bi-2-naphthol through enzymatic
resolution is very high. Although, commercially available enzymes such as lipases are
used for enantioselective hydrolysis of 1,1 '-bi-2-naphthol ester, enantiomeric excess is far
from desirable.
Asymmetric oxidative coupling is scientifically interesting and demonstrated by
using Camellia sinensis cell culture or horseradish peroxidase. However, enantiomeric
excess is far from satisfactory (Tetrahedron Lett. 2002, 43, 8499; Tetrahedron Lett. 1997.
38.5695)
II) Chemical resolution:
Resolution of (RS)-1,1'-bi-2-naphthol via formation of diastereomeric inclusion
complexes with various chiral hosts is very well documented. Some of these methods

reportedly gave low enantiomerie excess. Furthermore, in many cases overall yield is low
thus rendering most methods economically unfeasible.
More details about literature methods are discussed hereinafter.
Chiral amide derivatives of succinic acid and tartaric acid are used for resolution
of (RS)-1,1'-bi-2-naphthol. In the said method, synthesis of chiral amide derivatives is
tedious and requires POCl3. Furthermore to obtain optically pure 1,1'-bi-2-naphthol from
complex needs an additional step of forming complex with aqueous NH2NH2 followed by
decomposition in presence of dilute hydrochloric acid (J. Org. Chem. 1988. 53. 3607-
3609). Figure 1 gives the schematic representation of resolution of (RS)-1, l'-bi-2-
naphthol via amide derivatives of tartaric acid.
Resolution of (RS)-1,1'-bi-2-naphthol by forming inclusion complex with chiral
cinchonidium halidcs such as N-benzylcinchonidium and n-butyl cinchonidium bromide
(Tetrahedron Lett. 1995, 36, 7991-7994; J. Org. Chem 1994, 59, 5748-5751). chiral 1,2-
diaminocyclohexane (EP 471498), chiral m-tolyl methyl sulfoxide (Tetrahedron Lett.
1984. 25, 4929-4932) are not at all cost effective processes at industrial scale.
Resolution of (RS)-1,1-bi-2-naphthol by forming inclusion complex with L-
proline (Tetrahedron: Asymmetry, 1995, 6, 341-344); (R)-(α)-methyl benzylamine (J.
Org. Chem. 1999. 64, 7643-7645): (R)-2-aminobutanol (Synthesis 1990. 3. 222-223): (S)-
S-oxopyrrolidine-2-carboxanilidc (JP 08245460. Tetrahedron Lett. 2002. 43. 5273-5276)
have demonstrated poor enantiomeric excess and in most of these cases, overall yield is
very low. Hence, they cannot be used as an industrial process for obtaining optically pure
1,1'-bi-2-naphthol.
Resolution of (RS)-1,1'-bi-2-naphthol is also demonstrated by reaction with (R)-
menthyl chloroformate (J. Org. Chem, 1995, 60, 6599-6601); neomenthylthioacetic acid
chloride (Tetrahedron: Asymmetry 1995, 6, 111-114) and separation of diastereomers by
crystallization. However, lithium aluminum hydride, a hazardous chemical, is used to

decompose the complex, which is not operation friendly to handle at large scale. Hence it
cannot be used as an industrial process for obtaining optically pure 1,1'-bi-2-naphthol.
Moreover, cost per unit kg of final product is also high. Figure 2 gives the schematic
representation of resolution of (RS)-1,1'-bi-2-naphthol via (R)-menthyl chloroformate.
(III) Formation of phosphate ester diastereomeric inclusion complexes: Resolution of
(RS)-1,1'-bi-2-naphthol is also demonstrated by forming phosphate ester of (RS)-1,1'-bi-
2-naphthol followed by diastereomeric complex with optically pure α-
methylbenzylamine (J. Org. Chem. 1995. 60. 7364-7365) or L-menthol (J. Org. Chem.
1993. 58, 7313-7314), which is further separated by crystallization. Above said methods
use IiAlH4. which is not environmentally benign and require special handling conditions.
Hence it cannot be used as an industrial process for obtaining optically pure 1,1'-bi-2-
naphthol. Fig. 3. gives the schematic representation of resolution of (RS)-1,1'-bi-2-
naphthol via phosphate ester diastereomeric complex with chiral α-methyl benzyl amine.
IV) Formation of borate ester diastereomeric inclusion complexes: Resolution of
(RS)-1,1-bi-2-naphthol is also demonstrated by forming borate ester of (RS)-1,1'-bi-2-
naphthol and further treating with (R)-α-methylbenzylamine (J. Org. Chem. 1999. 64,
7643-7645); quinine (CN 1097728); TMEDA (Tetrahedron: Asymmetry 1996. 7. 2471-
2474) or L-Proline to obtain diastereomeric complex (Tetrahedron: Asymmetry 1998, 9,
39851, which is subsequently separated by crystallization. Most of the above methods
have demonstrated poor enantiomeric excess and overall yield is also very low. Hence
these cannot be used as industrial processes for obtaining optically pure l.l*-bi-2-
naphthol. Fig. 4. represents the schematic representation of the resolution of (RS)-\A'~
bi-2-naphthol via borate ester complex.
(V) Conglomerate separation: Tocla et al., reported the process for resolution of (RS)-
1,1'-bi-2-naphthol through inclusion complex formation with racemic or achiral
ammonium salts and transformation of complex into a conglomerate (Tetrahedron. 60.
2004; 7767-7774). WO 99/12623 describes the process for separation of (RS)-1,1'-bi-2-

naphthol by forming inclusion complex with A-methyl pyrrolidine and subsequent
conglomerate separation.
VI) Asymmetric Synthesis: US Patent 2005/0256345 describes the process for
asymmetric oxidative coupling of 2-naphthol in presence oi" vanadium complex. Egami
and Katsuki have reported iron catalyzed asymmetric aerobic oxidative coupling of 2-
naphthol (J. Am. Chem. Soc. 2009, 131, 6082-6083). Rate of reaction of vanadium
complex based asymmetric oxidation is very slow whereas iron catalyzed asymmetric
coupling reports poor enantiomeric excess.
US 6570036 describes the co crystallisation process for separation of racemic
naphthylethyl amine with (S)-ibuprofen and (S)-diacetone ketogulonic acid. However,
there is no embodiment of single crystal data. Powder X-ray diffraction analysis and
hydrogen bond interaction pattern for co-crystal.
It is evident from prior art that there is a need for an eco-friendly, "green", cost
effective, easy-to-operate industrial-scale synthesis of optically pure compound viz. (S)-
(-)-1,1'-bi-2-naphthol and (R)(+)-1,1'-bi-2-naphthol.
This invention provides that.
Summary of Invention:
The present invention is directed towards the method for preparation of
enantiomerically pure (S)-(-)-1,1 '-bi-2-naphthol and (R)-(+)-1,1'-bi-2-naphthol from (RS)-
1,1'-bi-2-naphthol (I) through formation of co-crystal with sequential addition of desired
optically pure γ-amino acid derivatives.

Co-crystal is defined as a crystal that contains two different molecules as a
complex held together by H-bonds, π-stacking or van der Waals forces (both molecules
are solids at ambient temperature) and co-crystal design such as crystal engineering and
supramolecular chemistry define it as consequence of molecular recognition events
between different molecular species (J. Pharm Sci 2006, 95. 499-516: Crystal kngg.
Commun. 2003, 5, 466-67; J. Chem. Soc: Chem. Comm. 1990, 589-591).
The method of manufacturing essentially consists of addition of a particular pure
diaslereomer of 3-[(1-phenyl ethylamino)-methyl]-hexanoic acid to a mixture of racemic
(RS)-1,1'-bi-2-naphthol [I] in methanol, wherein only one form of enanliomerically pure
l.l"-bi-2-naphthol forms a 1:1 co-crystal with the said optically pure y-amino acid
derivative. The co-crystal thus formed crystallizes out leaving the other antipode of 1,1'-
bi-2-naphthol in the mother liquor. Said co-crystal is then clarified from the mother liquor
by using techniques known in the art like filtration, centrifugation, decanlation etc.
The mother liquor, which contains the other antipode of 1,1 "-bi-2-naphthol, is
treated with the other antipode of optically pure y-amino acid derivative to form a similar
1:1 co-crystal.
The co-crystal is then decomposed with a hydrogen ion source like a Brønsted
acid such as dilute hydrochloric acid, dilute sulfuric acid, acetic acid etc. to obtain
optically pure l.l'-bi-2-naphthol. y-amino acid is recovered by neutralizing the acid
aqueous solution with sodium bicarbonate and reused, thereby making the whole process
very cost effective and easily operable.
When (RS)-1,1'-bi-2-naphthol [I] is reacted with (S,S)-3-[(1-phenyl ethylamino)-
methyl]-hexanoic acid [II],


there is formation of the easily separable co-crystal with (S-)(-)-1,1'-bi-2-
naphthol, which is separated by filtration, leaving behind (R)-(+)-1,1'-bi-2-naphthol in
mother liquor.
Further, mother liquor is reacted with (R,R)-3-[(1-phenyl ethylamino)-methyl]-
hexanoic acid [III].

which forms the easily separable co-crystal with (R)(+)-1,1'-bi-2-naphthol and is
separated by filtration.
The co-crystals thus obtained i.e. (S,S)-3-[(1-phenyl ethylamino)-methyl]-
hexanoic acid: (S)-(-)-1,1'-bi-2-naphthol [IV] and (R,R)-3-f(1-phenyl ethylamino)-
methyl]-hexanoic acid: (R)-(+)-1,1'-bi-2-naphthoI [V] are treated separately with dilute

hydrochloric acid to obtain (S) and (R) optically pure 1,1'-bi-2-naphthol respectively. The
% ee of the (R)-(+)-1,1'-bi-2-naphthol and (S)(-)-1,1'-bi-2-naphthol have been found to
be min of 99%.

Single crystal X-ray diffraction pattern analysis of co-crystal (.S,.V)-3-[(l-phenyl
ethylamino)-methyll-hexanoic acid: (S)-(-)-1,1'-bi-2-naphthol [IV] shows that the
composition is 1:1.
When (RS)-1,1'-bi-2-naphthol is reacted with (R,S)-3-](1-phenyl ethylamino)-
methyl]-hcxanoic acid [VI].


there is formation of the easily separable co-crystal with (S)-(-)-1,1'-bi-2-naphthol
which is separated by filtration, leaving behind (R)-(+)-1,1 '-bi-2-naphthol in the mother
liquor.
Further, mother liquor (filtrate) is reacted with (S,R)-3-[(1-phenyl ethylamino)-
mcthyl]-hexanoic acid [VII],

which forms the easily separable co-crystal with (R)-(+)-1,1'-bi-2-naphthol and is
separated by filtration.
The co-crystals thus obtained i.e. (R,S)-3-[(1-phenyl ethylamino)-methyl]-
hexanoic acid: (S)-(-)-1,1'-bi-2-naphthol [VIII] & (S,R)-3-[(1-phenyl ethylamino)-
methyl]-hexanoic acid: (R)-(+)-1,1'-bi-2-naphthol [IX] are treated with dilute
hydrochloric acid to obtain (S)-(-)-1,1'-bi-2-naphthol and (R)-(+)-1,1'-bi-2-naphthol

respectively. The % ee of the (R)-(+)-1,1'-bi-2-naphthol and (S)-(-)-1,1'-bi-2-naphthol
have been found to be min of 95 %.

Single crystal X-ray diffraction pattern analysis of co-crystal (R,S)-3-[(1-phenyl
ethylamino)-methylJ-hexanoic acid: (S)-(-)-1,1'-bi-2-naphthoI [VIII] shows that the
composition is 1:1.
Brief Description of Accompanying drawings
Figure 1: Schematic representation of resolution of (RS)-1,1'-bi-2-naphthol via
amide derivatives of tartaric acid
Figure 2: Schematic representation of resolution of (RS)-1,1'-bi-2-naphthol via
(R)-menthyl chloroformate

Figure 3: Schematic representation of resolution of (RS)-1,1-bi-2-naphthol via
phosphate ester diastereomeric complex with chiral (α)-methyl benzyl amine
Figure 4. Schematic representation of the resolution of (RS)-1,1'-bi-2-naphthol
via borate ester complex
Figure 5: ORTEP diagram of the single crystal of the co-crystal [IV]
Figure 6: Diagram of the single crystal of the co-crystal [VIII]
Figure 7. Schematic representation of synthesis of compound [II] and [VI]
Figure 8. Schematic representation of synthesis of compound [III] and [VII]
Figure 9. Schematic representation of synthesis of compound [XVII] and [XVIII]
Figure 10: PXRD of co-crystal of (S,S)-3-](1 -phenyl ethylamino)-mcthyl ]-
hexanoic acid : (S)-1,1'-bi-2-naphthol [VI]
Figure 11: PXRD of co-crystal of (R,S)-3-[(1 -phenyl ethylamino)-methyl]-
hexanoic acid : (S)- 1,1'-bi-2-naphthol [VIII]
Figure 12: PXRD of co-crystal of (R,R)-3-[(1 -phenyl ethylamino)-methyl]-
hexanoic acid : (R)-1,1 '-bi-2-naphthol [V]
Figure 13: PXRD of co-crystal of (S,R)-3-[(1-phenyl ethylamino)-methyl]-
hexanoic acid : (R)-1,1'-bi-2-naphthoI [IX]
Figure 14: PXRD of co-crystal of 5-methyl-3-[ ((R)-1-phenyl-ethylamino)-
melhyl]-hexanoic acid: (R)-1,1'-bi-2-naphthol
Detailed Description
The invention embodies method for obtaining optically pure enantiomers of
compound [I], having optical purity of > 99% with high yield.
According to one embodiment of the invention, chiral separation of compound |1]
to corresponding optically pure enantiomer is obtained via formation of co-crystal with
substituted γ-amino acids.

According to one embodiment of the invention, co-crystal composition is 1:1 for
which, the single crystal analysis details are given hereinafter.
Crystal structure of the single crystal of co-crystal [IV] is measured on Bruker
Smart Apex CCD diffractometer having software SHELXTL-PLUS at temperature 293
(2) K and wavelength 0.71073 A and θ range for data collection is 1.56 to 28.40°. Table 1
summarizes the crystal data and structure refinement and ORTEP diagram of the single
crystal of co-crystal [IV] is given in figure 5.



Flack parameter factor is normally used to estimate the absolute configuration of a
structure in single crystal structure analysis. To assign the correct absolute configuration,
the Fiack parameter value should be near to zero with small standard deviation and to
achieve that requires a heavy atom to be attached to the compound. In the said γ-amino
acid [II], there is no such heavy atom hence Flack parameter can not be used to assign the
configuration. Hence by applying Cahn-Ingold-Prelog priority rule, the absolute
configuration is defined. Stereochemistry of carbon atom 1 in [X] is "S" and it comes
from (.S")-a-methyl benzyl amine and on this basis, stereochemistry of carbon at 2 is
assigned as "S".

1M NMR data and FTIR of γ- amino acid confirm the above structure, i.e. Carbon atom 1
and 2 of (VII) are both in 'S' configuration.

FTIR (KBr pellets): 2960, 1623. 1547 cm-1;
1H NMR (CDCl3, 200 MHz): δ 0.84-0.86 (t, 3H). 1.13-1.18 (q, 2H). 1.21-1.26 (q. 2H).
1.69-1 70 (d, 3H), 2.14-2.18 (d, 2H), 2.51-2.58 (t, 211). 2.75-2.78 (d, 1H). 4.12-4.17 (q,
1H). 7.35-7.42 (m, 3H), 7.47-7.51 (m, 2H);
MS (EI): C15H23NO2: 249.17; [M+H]+ 250.20
The sodium salt of compounds [II], [III], [VI] and [VII] show an IR band at 1730
cm-1. indicating the presence of the free carboxylic acid. FTIR spectra of [II ], [III], [VI]
and [VII] show zwitterion patterns.
Powder X-ray diffraction data generated from single crystal of co-crystal (S,S)-3-
[(1-phenyl ethylamino)-methyl]-hexanoic acid:(S)-(-)-1,1'-bi-2-naphthol is same as
powder X-ray diffraction data obtained from bulk material.
Crystal structure of the single crystal of the co-crystal [VIII] is measured on
Eiruker Smart Apex CCD diffractometer having software SHELXTL-PLUS at
temperature 293 (2) K and wavelength 0.71073 Å and θ range for data collection is 1.56
to 28.40°. Table 2 summarizes the crystal data and structure refinement and ORTFP
diagram of the single crystal of co-crystal [VIII] is given in figure 6.



The said optically pure γ-amino acids are prepared by the procedure disclosed in
our co-pending patent application entitle "Novel method for preparation of
enantiomerically enriched and /or racemic γ -amino acids" and described hereinafter.
5-hydroxy-4-n-propyl-5H-furan-2-one [XIa] when reacted with (S)-(α)-methyl
benzyl amine [XII] gives the compound [XIII]. Hydrogenation of compound [XIII] in
iso-propanol gives the diastereomeric compounds [II] and [VI], which get separated
during the reaction. Compound [II] precipitates out from reaction, leaving compound
[VI] dissolved in the reaction media. Fig.7. gives the schematic representation.
5-hydroxy-4-n-propyl-5H-furan-2-one [XIa] when reacted with (R)-(α)-methyl
benzyl amine [XIV] gives the compound [XV]. Hydrogenation of compound [XIII] in
iso-propanol gives the diastereomeric compounds [111] and [VII], which arc separated
during the reaction. Compound [III] precipitates out from reaction leaving compound
[VII] dissolved in the reaction media. Fig.8. gives the schematic representation.
5-hydroxy-4-iso-butyl-5H-furan-2-one [XIb] when reacted with (R)-(α)-mcthyl
benzyl amine [XIV] gives the compound [XVI]. Hydrogenation of compound [XVI] in
iso-propanol gives mixture of diastereomeric compounds [XVII] and [XVIII]. Figure 9
gives the schematic representation.

Physical properties of compounds [II], [III], [VI] and [VII] are summarized in Table 3

Compound [II] with (S)-1,1'-bi-naphthol gives the co-crystal (S,S)-3-[(1 -phenyl
ethylamino)-methyl]-hexanoic acid: (S)-(-)-1,1'-bi-2-naphthol [IV] and compound [VI]
with (S)-(-)-1,1'-bi-naphthol gives (R,S)-3-[(l-phenylethylamino)-methyl]-hexanoic acid:
(S)-(-)-1,1'-bi-2-naphthol[VIII].
Compound [III] with (R)-1,1'-bi-naphthol gives the co-crystal (R,R)-3-[( 1 -phenyl
ethylamino)-methyl]-hexanoic acid: (R)-(+)-1,1'-bi-2-naphthol [V] and compound [VII]
with (R)-(+)-1,1'-bi-naphthol gives the co-crystal (S,R)-3-[(1-phenylethylamino)-
methyl]-hexanoic acid: (R)-(+)-1,1 '-bi-2-naphthol [IX].

Physical properties of co-crystals [IV], [V], [VIII] and [IX] are summarized in Table 4.



Table 5 gives the comparative data of FTIR spectra of free racemic (RS)-1,1'-b'-
2-naphthol [I]. co-crystal [(S,S)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid :(S)-(-)-
l.r-bi-2-naphthol) [IV] and (S,S)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid [II].

*FTIR absorption peak observed by preparing pellet of solid of respective
compound dispersed in dry potassium bromide.
Surprisingly it is observed that compound [1II] and compound [VII] are
diastereomers. where the stereo-configuration at benzylic center is same i.e. "R". When
these compounds are reacted with (R)-(+)-1,1'-bi-naphthol, they give the co-crystals [V]

and [IX] respectively. Similarly it is also observed that compound [II] and |VJJ arc
diastereomers. where the stereo-configuration at benzylic center is same i.e. "S". When
these compounds are reacted with (S)-(-)-1,r-bi-naphthol. they give the co-crystals [IV]
and [VIII] respectively.
Hence, it can be hypothesized that irrespective of stereo-configuration at alkyl
chain, stereo-configuration at benzylic center is the deciding factor for stereo specific co-
crystal formation. This postulation have been found true for 5-mcthyl-3-[((R)-1-phenyl-
ethylamino)-methyl]-hexanoic acid i.e. the diastereomeric mixture of compounds [XVII]
and [XVIII]. When the mixture is treated with (R)-(+)-1,1'-bi-naphthol it gives the co-
crystal 5-methyl-3-[((R)-l-phenyl-ethylamino)-methyl]-hexanoic acid : (R)-(+)-1.1'-bi-
naphthol, which precipitates out from the reaction media and similarly when
diastereomeric mixture of compounds [XVII] and [XVIII] is treated with (S)-(-)-1,1'-bi-
naphthol it remains dissolved in reaction media. Hence it could be a method for
resolution of (RS)-1,1'-bi-naphthol to obtain optically pure (S) or (R)-1,1'-bi-naphthol.
Powder x-ray diffraction pattern for co-crystal 5-methyl-3-[((R)-1-phenyl-
ethylamino)-methyl]-hexanoic acid (diastereomeric mixture of compound [XVII] and
[XVIII]): (R)-(+)-1,1'-bi-naphthol is given in Figure 14.
In all cases, the co-crystal formation of the optically active γ-amino acids with
compound [I] is carried out in an alcoholic solvent, preferably methanol.
In all cases, the co-crystal formation of compound [I] with optically active γ-
amino acids is carried out at a temperature range of 25-60° C, preferably at 50° C.
Molar ratio of optically pure y-amino acids to compound [I] varies from 0.5 to 1.5
mol equivalents, preferably 0.5 mol equivalent is used.

The co-crystals of compound [I] with optically active γ-amino acids are
decomposed in a biphasic mixture of ethyl acetate: dilute hydrochloric acid (1:1) at room
temperature.
The optically active γ-amino acids are recovered from the aqueous phase by
neutralizing the aqueous dilute hydrochloric acid with dilute sodium bicarbonate solution
and are reused.
Nomenclatures used for the compounds mentioned herein are as understood from
the CambridgeSoft® ChemOffice software ChemDraw Ultra version 6.0. J.
Analytical Methods:
The enantiomeric excess (ee) is determined by HPI.C using a Shimadzu IX 2010
system equipped with a chiral column (Chiral pak IA, 4.6mm x 250mm. 5µm), column
oven temperature 40 °C and UV visible detector (230 nm). Mobile phase is n-hexane (94)
:n-butanol (5) : ethanol (1): Trifluoacetic acid (0.3 mL) with flow rate 1 mL-, injection
volume 20 µl. NMR spectra are obtained at 200 and 400 MHz Bruker instruments, with
CDCl3 as solvent. Chemical shifts (S) are given in ppm relative to tetramethylsilane (δ=
0 ppm). IR spectra are recorded on Perkin Elmer Spectrum (Model: Spectrum 100) and
absorption bands are given in cm-1. DSC is recorded on Perkin Elmer model Diamond
DSC at the rate of 10 °C7min, and endothermic peak is recorded in ° C and ∆H is reported
in J/g.

Example 1: Synthesis of 5-hydroxy-4-n-propyl-5H-furan-2-one [XI]
(Reference: J. Org. Chem 1981,46,4889-4894)
Heptane (394 mL) and morpholine (127.5 mL) are introduced in a reactor while
stirring. The mixture is cooled to 0°C and glyoxylic acid (195 g. 150 mL. 50 wt% in water) is
added. The mixture is heated to 20°C during 1 hour and then n-valeraldehyde (148.8 mL) is
added. The reaction mixture is heated at 45°C during 20 hours. After cooling down to 20°C.
a 37% aqueous solution of hydrochloric acid (196.9 mL) is slowly added to the mixture,
which is then stirred during 2 hours.
After removal of the heptane phase, the aqueous phase is washed three times with
heptane. Di-iso-propyl ether is added to the aqueous phase. The organic phase is removed
and the aqueous phase further extracted with di-iso-propyl ether (2x). The diisopropyl ether
layers are combined, washed with brine and then dried under reduced pressure. After
evaporation of the solvent, 100.0 g of 5-hydroxy-4-n-propyl-5H-furan-2-onc are obtained as
light brown oil.
FTIR (neat): 3367, 1735 cm-1.
1H NMR (CDCl3, 200 MHz): δ 0.93-1.00 (t, 3H), 1.56-1.67 (q, 2H). 2.31-2.43 (q. 211), 5.81
(s. lH).6.02(s. lH).
MS (EI): C7H10O3: 142.06; [M+H]+: 142.93.
Example 2: Synthesis of 5-hydroxy-1-[(S)-phenyl-ethyl]-4-n-propyl-1,5-dihydro-pyrrol-
2-onc [XIII]
5-hydroxy-4-n-propyl-5H-furan-2-one (10.0 g) is dissolved in iso-propanol (100 mL)
and (S)-α-methyl benzyl amine (8.5 g) is added to it at room temperature. The mixture is
stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC.
1:1 ethyl acetate:hexane), the solvent is evaporated under reduced pressure in a rotary
evaporator to afford 5-hydroxy-1-[(S)-phenyl-ethyl]-4-n-propyl-1,5-dihydro-pyrrol-2-one as
dark yellow oil (16.5 g).

FTIR(neat): 3321. 1749, 1165 cm-1.
1H NMR (CDCl3, 200 MHz): δ 0.86-0.94 (t, 3H), 1.31-1.37 (t, 3H). 1.43-1.57 (m, 211), 2.12-
2.39 (m. 2H). 4.27-4.30 (d, 1H), 5.15 (s, 1H), 5.70 (s, 1H). 7.25-7.34 (m, 5H).
MS (EI): C15H19NO2: 245.14: [M+H]+: 246.51.
Example 3: Synthesis of 5-hydroxy-1-[(R)-phenyl-ethyl]-4-n-propyl-1,5-dihydro-pyrrol-
2-one [XV]
5-hydroxy-4-n-propyl-5H-furan-2-one (10.0 g) is dissolved in iso-propanol (100 mL)
and (R)-α-methyl benzyl amine (8.5 g) is added to it at room temperature. The mixture is
stirred at room temperature for 1 hour. After completion of the reaction (monitored by TI.C.
1:1 ethyl acetate:hexane), the solvent is evaporated under reduced pressure in a rotary
evaporator to afford 5-hydroxy-1-[(R)phenyl-ethyl]-4-n-propyl-1,5-dihydro-pyrrol-2-one as
dark yellow oil (16.5 g).
FTIR (neat): 3321, 1749. 1165 cm-1.
1H NMR (CDCl3,200 MHz): δ 0.86-0.94 (t, 3H), 1.31-1.37 (t, 3H), 1.43-1.57 (m, 2H), 2.12-
2.39 (m, 2H), 4.27-4.30 (d. 1H), 5.15 (s, 1H), 5.70 (s, 1H). 7.25-7.34 (m, 5H).
MS (EI): C15H19NO2: 245.14; [M+H]4: 246.51.
Example 4: Hydrogenation of 5-hydroxy-1-[(S)-phenyl-ethyl]-4-n-propyl-1,5-
dihydro-pyrrol-2-onc [XIII] with Pd/C
5-hydroxy-l-[(S)-phenyl-ethyl]-4-n-propyl-1,5-dihydro-pyrrol-2-one (16.5 g) is
dissolved in iso-propanol (100 mL) in a Parr autoclave reactor followed by addition of 50
% wet palladium-on-carbon (Pd/C) at 10 % catalyst loading. Reactor is purged with
hydrogen gas twice and then 3 kg/cm2 hydrogen pressure is maintained. Reaction is
monitored by TLC [chloroform: methanol (9:1)J. After complete consumption of starling
material, the reaction is stopped. In the reaction, diastereomers separate; (S,S)-3-[(1-
phenyl ethylamino)-methyl]-hexanoic acid precipitates out from the reaction media and

(R,S)-3-[(1 -phenyl ethylamino)-methyl]-hexanoic acid remains dissolved in the reaction
media.
After completion of reaction, the reaction mixture is filtered and filtrate is
concentrated under vacuum to obtain a semi solid material, which is suspended in
cyclohexane (300 mL) and stirred overnight to yield 6.5 g of (R,S)-3-[(1-phenyl
ethylamino)-methyl]-hexanoic acid as a off-white solid obtained after vacuum filtration.
Filtered cake contains Pd/C and (S,S)-3-[(1-phenyl ethylamino)-methyl]-hexanoic
acid which is suspended in 50 ml methanol and stirred for 20 min to dissolve (S,S)-3-f(1-
phenyl ethylamino)-methyl]-hexanoic acid. Pd/C is separated by filtration. Filtrate is
concentrated under vacuum to obtain 8.0 g of (S,S)-3-[(1-phenyl ethylamino)-methyl]-
hexanoic acid as a white solid.
(S,S)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (II]:
FTIR (KBr pellets): 2960, 1623, 1547 cm-1;
1H NMR (CDCl3, 200 MHz): δ 0.84-0.86 (t, 3H). 1.13-1.18 (q. 211), 1.21-1.26 (q. 211).
1.69-1.70 (d, 3H), 2.14-2.18 (d, 2H), 2.51-2.58 (t, 2H), 2.75-2.78 (d. 1H), 4.12-4.17 (q.
1H). 7.35-7.42 (m, 3H). 7.47-7.51 (m, 2H); MS (E1): C15H23NO2: 249.17; [M+H]:
250.20
DSC (10 °C/min): Peak at 147.16°C
(R,S)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid [VI|:
FTIR (KBr pellets): 2956, 1619. 1549, 1400 cm-1;
1H NMR (CDCl3, 200 MHz): S 0.76-0.79 (t, 3H), 1.14-1.23 (m,4H). 1.66-1.68 (d. 311),
2.26-2.30 (m. 2H), 2.53-2.59 (t, 211), 2.77-2.80 (d, 1H), 4.06-4.11 (q. 1H), 7.31-7.57 (m.
5H);
MS (EI): C15H23NO2: 249.17; [M+H]+: 250.05.
DSC (10 °C/min): Peak at 120.1 °C
Example 5: Hydrogenation of 5-hydroxy-1-[(R)-phcnyl-ethyl]-4-n-propyl-1,5-
dihydro-pyrrol-2-one [IX] with Pd/C

5-hydroxy-1 -[(R)-phenyl-ethyl]-4-n-propyl-1,5-dihydro-pyrrol-2-one
(16.5 g) is dissolved in iso-propanol (100 mL) in a Parr autoclave reactor followed by
addition of 50 % wet palladium-on-carbon (Pd/C) at 10 % catalyst loading. Reactor is
purged with hydrogen gas twice and then 3 kg/cm2 hydrogen pressure is maintained.
Reaction is monitored by TLC [chloroform: methanol (9:1)|. After complete
consumption of starting material, the reaction is stopped. In the reaction, diastereomers
separate; (R,R)-3-[(1-phenyl ethylamino)-methylJ-hexanoic acid precipitates out from the
reaction media and (S,R)-3-[(1-phenyl ethylamino)-methyl]-hcxanoic acid remains
dissolved in the reaction media.
After completion of reaction, the reaction mixture is filtered and filtrate is
concentrated under vacuum to obtain a semi solid material, which is suspended in
cyclohexane (300 mL) and stirred overnight to yield 6.0 g of (S,R)-3-[(1-phenyl
ethylamino)-methyl]-hexanoic acid as a off-white solid obtained after vacuum filtration.
Filtered cake, which contains Pd/C and (R,R)-3-[( 1 -phenyl ethylamino)-methylJ-
hexanoic acid is suspended in 50 ml methanol and stirred for 20 min to dissolve (R,R)-3-
1(1 -phenyl ethylamino)-methyl|-hexanoic acid. Pd/C is separated by filtration. Filtratc is
concentrated under vacuum to obtain 8.0 g of (R,R)-3-1(1-phenyl ethylamino)-methyl]-
hexanoic acid as white solid.
(R,R)-3-[(1 -phenyl ethylamino)-methyl]-hexanoic acid (III|:
FTIR (KBr pellets): 2958, 1621, 1548, 1397 cm-1.
1H NMR (CDCl3, 200 MHz): δ 0.80-0.87 (t, 3H), 1.17-1.22 (m, 4H), 1.67-1.70 (d. 3H),
2.13-2.19 (d, 211). 2.44-2.61 (t, 2H), 2.74-2.80 (d, 1H), 4.11-4.20 (q. 1H), 7.30-7.54 (m,
511).
MS (El): C15H23NO2: 249.17; [M+H]+: 250.03.
DSC (10 °C7min): Peak at 148.11 °C
(S,R)-3-1(1-phenyl ethylamino)-methyl]-hexanoic acid [VII]:
FTIR (KBr pellets): 2957, 1620. 1550, 1399 cm-1.

1H NMR (CDCl3, 200 MHz): δ 0.75-0.81 (t, 3H), 1.18-1.41 (m, 4H). 1.65-1.69 (d. 311),
2.20-2.33 (m, 2H). 2.49-2.60 (t. 2H). 2.76-2.82 (d. 1H). 4.07-4.17 (q. 1H). 7.32-7.54 (m.
511).
MS (EI): C15H23NO2: 249.17; [M+H]+: 250.50.
DSC (10 °C/min): Peak at 119.3°C
Example 6: Diastereomeric co-crystal formation of (S,S)-3-[(1-phenyl ethylamino)-
methyl]-hexanoic acid with (S)-1,1'-bi-2-naphthol
(S,S)3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (1.0 g) is dissolved
in methanol (20 mL) and (.V)-1,1'-bi-2-naphthol (1.15 g) is added to it at room
temperature. The solution is stirred at 50 °C for 1 hour; during which time solid
precipitate comes out from the reaction mixture. Reaction mixture is allowed to cool to
room temperature and filtered under reduced pressure to obtain 1.55 g of the complex.
Fig 10. PXRD of co-crystal of (S,S)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid :
(S)-1,1'-bi-2-naphthol[Vl]
DSC (10 °C/min): Peak at 185.82 °C.
Example 7: Diastereomeric co-crystal formation of (S,S)-3-[(1-phenyl ethylamino)-
methyI|-hexanoic acid with (R)-1,1'-bi-2-naphthol
(S,S)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (1.0 g) is dissolved in
methanol (20 mL) and (R)-1,1'-bi-2-naphthol (1.15 g) is added to it at room temperature.
The mixture is stirred at 50 °C for 1 hour. Reaction mixture is allowed to cool to room
temperature and solvent is evaporated under vacuum to obtain solid (2.0 g): PXRD
analysis of obtained solid shows that it is amorphous in nature.
Example 8: Diastereomeric co-crystal formation of (R,S)-3-[(1-phenyl ethylamino)-
methyll-hexanoic acid with (S)-1,1'-bi-2-naphthol
(R,S)3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (1.0 g) is dissolved
in methanol (20 mL) and (S)-1,1'-bi-2-naphthol (1.15 g) is added to it at room

temperature. The mixture is stirred at 50 °C for 1 hour, during which time solid
precipitate comes out from the reaction mixture. Reaction mixture is allowed to cool to
room temperature and filtered under reduced pressure to obtain 1.45 g of the complex.
Fig 11. PXRD of co-crystal (R,S)-3-[(1-phenyl ethylamino)-rnethyl]-hexanoic acid : (S)-
1,1'-bi-2-naphthol[VIII].
DSC (10 °C/min): Peak at 177.69 °C.
Example 9: Diastereomeric co-crystal formation of (R,S)-3-[(1-phenyl cthylamino)-
methyl]-hexanoic acid with (R)-1,1'-bi-2-naphthol
(R,S)3-[(1 -phenyl ethylamino)-methyl]-hexanoic acid (1.0 g) is dissolved
in methanol (20 mL) and (R)-1,1'-bi-2-naphthol (1.15 g) is added to it at room
temperature. The mixture is stirred at 50 °C for 1 hour. Reaction mixture is allowed to
cool to room temperature and solvent evaporated under vacuum to obtain solid; PXRD
analysis of obtained solid shows that it is amorphous in nature.
Example 10: Diastereomeric co-crystal formation of (R,R)-3-[(1-phenyl
ethylamino)-methyl]|-hexanoie acid with (R)-1,1'-bi-2-naphthol
(R,R)-3-[(1 -phenyl ethylamino)-methyl]-hexanoic acid (1.0 g) is dissolved
in methanol (20 mL) and (R)-1,1'-bi-2-naphthol (1.15 g) is added to it at room
temperature. The mixture is stirred at 50 °C for 1 hour, during which time solid
precipitate comes out from the reaction mixture. Reaction mixture is allowed to cool to
room temperature and filtered under reduced pressure to obtain 1.5 g of the complex. Fig
12. PXRD of co-crystal (R,R)-3-[(1-phenyl ethylamino)-mcthyl]-hexanoic acid : (R)-1,1'-
bi-2-naphthol [V].
DSC (10 °C7min): Peak at 186.71 °C
Example 11. Diastereomeric co-crystal formation of (R,R)-3-[(l-phenyl ethylamino)-
methyl]-hexanoic acid with (S)-1,1'-bi-2-naphthol

(R.R)-3-[( 1 -phenyl ethylamino)-methyl]-hexanoic acid (1.0 g) is dissolved in
methanol (20 ml.) and (S)-1,1'-bi-2-naphthol (1.15 g) is added to it at room temperature. The
mixture is stirred at 50 °C for 1 hour. Reaction mixture is allowed to cool to room
temperature and solvent evaporated under vacuum to obtain solid; PXRD analysis of
obtained solid shows that it is amorphous in nature.
Example 12: Diastereomeric co-crystal formation of (S,R)-3-[(1-phenyl ethylamino)-
methyl|-hexanoic acid with (R)-1,1'-bi-2-naphthol
(S,R)-3-[(1 -phenyl ethylamino)-methyl]-hcxanoic acid (1.0 g) is dissolved
in methanol (20 mL) and (R)-1,1'-bi-2-naphthol (1.15 g) is added to it at room
temperature. The mixture is stirred at 50 "C for 1 hour, during which time solid
precipitate comes out from the reaction mixture. Reaction mixture was allowed to cool to
room temperature and filtered under reduced pressure to obtain 1.6 g of the complex. Fig
13. PXRD of co-crystal (S,R)-3-[(1-phenyl ethylamino)-methyll-hexanoic acid : (R)-1,1'-
bi-2-naphthol [IX].
DSC (10 °C/min): Peak at 172.62 °C.
Example 13. Diastereomeric co-crystal of (S,R)-3-1(1-phenyl ethylamino)-methyl]-
hexanoic acid with (S)-1,1'-bi-2-naphthol
(R,R)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (1.0 g) is dissolved
in methanol (20 mL) and (S)-1,1'-bi-2-naphthol (1.15 g) is added to it at room
temperature. The mixture is stirred at 50 C for 1 hour. Reaction mixture is allowed to
cool to room temperature and solvent evaporated under vacuum to obtain solid: PXRD
analysis of obtained solid shows that it is amorphous in nature.
Example 14: Separation of (S)-1,1'-bi-2-naphthol from (RS)-1,1'-bi-2-naphthol via
formation of diastereomeric co-crystal with (S,S)-3-[(1-phenyl ethylamino)-methyl]-
hexanoic acid.

(S,S)3-[(1 -phenyl ethylamino)-methyl]-hexanoic acid (5.0 g) is dissolved in
methanol (20 mL) and (RS)-1,1'-bi-2-naphthol (5.75 g) is added to it at room temperature.
The mixture is stirred at 50 °C for 1 hour, during which time solid precipitate comes out from
the reaction mixture. Reaction mixture is allowed to cool to room temperature and filtered
under reduced pressure to obtain 3.5 g of solid complex. Complex is suspended in the
biphasic mixture of ethyl acetate (20 ml) and 1N hydrochloric acid (20 ml) and stirred for 30
to 45 min to decompose the complex. Aqueous phase is washed with 10 ml. ethyl acetate.
Organic phases are mixed together and washed with brine, followed by drying over sodium
sulfate. Solvent is evaporated under vacuum to obtain optically pure (S)-1,1'-bi-2-naphthol
(1.5 g) having 99 % ee.
The acid aqueous solution which contains hydrochloride salt of (S,S)3-[(1-phenyl
ethylamino)-methyl]-hexanoic acid is neutralized with dilute solution of sodium bicarbonate
to recover the (S,S)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (0.8 g).
Example 15: Separation of (5)-1,1'-bi-2-naphthol from (RS)-:1,1'-bi-2-naphthol via
formation of diastereomeric co-crystal with (R,S)-3-[(1-phenyl ethylamino)-methyl]-
hexanoic acid
(R,S)-3-[(1-phenyl ethyIamino)-methyl]-hexanoic acid (5.0 g) is dissolved in
methanol. (20 mL) and (RS)-1,1'-bi-2-naphthol (5.75 g) is added to it at room temperature.
The mixture is stirred at 50 °C for 1 hour, during which time solid precipitate comes out from
the reaction mixture. Reaction mixture is allowed to cool to room temperature and filtered
under reduced pressure to obtain 3.7 g of solid complex. Complex is suspended in the
biphasic mixture of ethyl acetate (20 mL) and 1 A' hydrochloric acid (20 ml.) and stirred for
30 to 45 min to decompose the complex. Aqueous phase is washed with 10 mL ethyl acetate.
Organic phases are mixed together and washed with brine, followed by drying over sodium
sulfate. Solvent is evaporated under vacuum to obtain optically pure (S')-1,1'-bi-2-naphlhol
(1.56 g) having 95% ee.

The acid aqueous solution which contains hydrochloride salt of (R,S)-3-[(1-phenyl
ethylamino)-methylJ-hexanoic acid is neutralized with dilute solution of sodium bicarbonate
to recover the (R,S)-3-f(1 -phenyl ethylamino)-methyl]-hexanoic acid (0.85 g).
Example 16: Separation of (R)-1,1'-bi-2-naphthol from (RS)-l,1'-bi-2-naphthol via
formation of diastereomeric co-crystal with (R,R)-3-[(1-phenyl ethylamino)-methyl]-
hexanoic acid
(R,R)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (5.0 g) is dissolved in
methanol (20 ml.) and (RS)-1,1'-bi-2-naphthol (5.75 g) is added to it at room temperature.
The mixture is stirred at 50 °C for 1 hour, during which time solid precipitate comes out from
the reaction mixture. Reaction mixture is allowed to cool to room temperature and filtered
under reduced pressure to obtain 3.6 g of solid complex. Complex is suspended in the
biphasic mixture of ethyl acetate (20 ml.) and 1N hydrochloric acid (20 ml.) and stirred for
30 to 45 min to decompose the complex. Aqueous phase is washed with 10 mL ethyl acetate.
Organic phases are mixed together and washed with brine, followed by drying over sodium
sulfate. Solvent is evaporated under vacuum to obtain optically pure (R)-1.1'-bi-2-naphthol
(1.5 g) having 99 % ee.
The acid aqueous solution which contains hydrochloride salt of (R,R)-3-[(1-phenyl
ethylamino)-methyl|-hexanoic acid is neutralized with dilute solution of sodium bicarbonate
to recover the (R,R)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (0.9 g).
Example 17: Separation of (R)-1,1'-bi-2-naphthol from (RS)-1,1'-bi-2-naphthol via
formation of diastereomeric co-crystal with (S,R)-3-[(1-phenyl ethylamino)-methyl]-
hexanoic acid.
(S,R)-3-[( 1 -phenyl elhylamino)-methyl]-hexanoic acid (5.0 g) is dissolved in
methanol (20 mL) and (RS)-1,1'-bi-2-naphthol (5.75 g) is added to it at room temperature.
The mixture is stirred at 50 °C for 1 hour, during which time solid precipitate comes out from
the reaction mixture. Reaction mixture is allowed to cool to room temperature and filtered

under reduced pressure to obtain 3.6 g of solid complex. Complex is suspended in the
biphasic mixture of ethyl acetate (20 mL) and 1N hydrochloric acid (20 ml.) and stirred for
30 to 45 min to decompose the complex. Aqueous phase is washed with 10 ml. ethyl acetate.
Organic phases are mixed together and washed with brine, followed by drying over sodium
sulfate. Solvent is evaporated under vacuum to obtain optically pure (R)-1,1'-bi-2-naphthol
(1.25 g) having 95 % ee.
The acid aqueous solution which contains hydrochloride salt of (R,R)-3-[( 1 -phenyl
ethylamino)-methyl]-hexanoic acid is neutralized with dilute solution of sodium bicarbonate
to recover the (S,R)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (0.75 g).
Example 18: Resolution of (RS)-1,1'-bi-2-naphthol via formation of diastcreomeric
co-crystals by sequential addition of (S,S)-3-[(1-phenyl ethylamino)-methyl]-
hexanoic acid and (R,R)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid.
(R,S)-]-1,1'-bi-2-naphthol (5.75 g) is dissolved in methanol (20 ml.) and (SS)-3-[(1-
phcnyl ethylamino)-methylJ-hexanoic acid (2.5 g) is added to it at room temperature. The
mixture is stirred at 50 °C for 1 hour, during which time solid precipitate comes out from the
reaction mixture. Reaction mixture is allowed to cool to 5 °C and filtered under reduced
pressure to obtain 4.1 g of the complex.
The complex is suspended in the biphasic mixture of ethyl acetate (20 mL) and 1N
hydrochloric acid (20 ml.) and stirred for 30 to 45 min to decompose the complex. Aqueous
phase is washed with 10 ml. ethyl acetate. Organic phases are mixed together and washed
with brine, followed by drying over sodium sulfate. Solvent is evaporated under vacuum to
obtain optically pure (S)-1,1'-bi-2-naphthol (2.3 g) having 99 % ee (yield 80%).
The acid aqueous solution which contains hydrochloride salt of (S,S)-3-[(1-phenyl
ethylamino)-methyl]-hexanoic acid is neutralized with dilute solution of sodium bicarbonate
to recover the (S,S)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (0.95 g).

(R,R)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (2.5 g) is added to the filtrate
at room temperature. The mixture is stirred at 50 °C for 1 hour, during which time solid
precipitate comes out from the reaction mixture. Reaction mixture is allowed to cool to 5 °C
and filtered under reduced pressure to obtain 4.8 g of solid complex. Complex is further
suspended in 10 mL methanol and stirred for 1 h at 50 oC. Reaction mixture is allowed to
cool to room temperature and filtered under reduced pressure to obtain 4.0 g of solid
complex.
The complex is suspended in the biphasic mixture of ethyl acetate (20 mL) and 1N
hydrochloric acid (20 mL) and stirred for 30 to 45 min to decompose the complex. Aqueous
phase is washed with 10 mL ethyl acetate. Organic phases are mixed together and washed
with brine, followed by drying over sodium sulfate. Solvent is evaporated under vacuum to
obtain optically pure (R)-1,1'-bi-2-naphthol (2.0 g) having 99 % ee (yield 70%).
The acid aqueous solution which contains hydrochloride salt of (R,R)-3-[(1-phenyl
ethylamino)-methyl]-hexanoic acid is neutralized with dilute solution of sodium bicarbonate
to recover the (R,R)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (0.8 g).
Example 19: Resolution of (RS)-1,1'-bi-2-naphthol via formation of diastereomeric
co-crystals by sequential addition of (R,S)-3-[(1-phenyl ethylamino)-methyl]-
hexanoic acid and (S,R)-3-[(1 -phenyl ethylamino)-methyl]-hexanoic acid.
(RS)-1,1'-bi-2-naphthol (5.75 g) is dissolved in methanol (20 mL) and (R,S)3-[(1-
phenyl ethylamino)-methyll-hexanoic acid (2.5 g) is added to it at room temperature. The
mixture is stirred at 50 °C for 1 hour, during which time solid precipitate comes out from the
reaction mixture. Reaction mixture is allowed to cool to room temperature and filtered under
reduced pressure to obtain 3.5 g of the complex.
The complex is suspended in the biphasic mixture of ethyl acetate (20 mL) and 1 .V
hydrochloric acid (20 mL) and stirred for 30 to 45 min to decompose the complex. Aqueous
phase is washed with 10 mL ethyl acetate. Organic phases are mixed together and washed

with brine, followed by drying over sodium sulfate. Solvent is evaporated under vacuum to
obtain optically pure (S)-1,1'-bi-2-naphthol (2.0 g) having 98 % ee (yield 70%).
The acid aqueous solution which contains hydrochloride salt of (R,S)-3-[(1 -phenyl
ethylamino)-mcthyl]-hexanoic acid is neutralized with dilute solution of sodium bicarbonate
to recover the (R.S)-3-[(1 -phenyl ethylamino)-methylJ-hexanoic acid (0.8 g).
(S,R)-3-[(1-phenyl ethylamino)-methyl]-hexanoic acid (2.5 g) is then added to the
filtrate at room temperature. The mixture is stirred at 50 °C for 1 hour, during which time
solid precipitate comes out from the reaction mixture. Reaction mixture is allowed to cool to
room temperature and filtered under reduced pressure to obtain 3.7 g of solid complex.
The complex is suspended in the biphasic mixture of ethyl acetate (20 mL) and l.V
hydrochloric acid (20 mL) and stirred for 30 to 45 min to decompose the complex. Aqueous
phase is washed with 10 mL ethyl acetate. Organic phases are mixed together and washed
with brine, followed by drying over sodium sulfate. Solvent is evaporated under vacuum to
obtain optically pure (R)-1,1'-bi-2-naphthol (1.7 g) having 98 % ee (yield 65%).
The acid aqueous solution which contains hydrochloride salt of (S,R)-3-[(1-phenyl
ethylamino)-methyl]-hexanoic acid is neutralized with dilute solution of sodium bicarbonate
to recover the (S,R)-3-[(1 -phenyl ethylamino)-methyl]-hexanoic acid (0.8 g).
Example 20: Co-crystal formation of 5-methyl-3-[((R)-1-phenyl-ethylamino)-
methyl]-hexanoic acid with (R)-1,1'-bi-2-naphthol
5-Methyl-3-[((R)-l-phenyl-ethylamino)-methyl]-hexanoic acid (0.2 g) is
dissolved in methanol (5 mL) and (R)-1,1'-bi-2-naphlhol (0.25 g) is added to it at room
temperature. The mixture is stirred at 50 °C for 5 h. Reaction mixture is allowed to cool
to room temperature and kept over night to obtain co-crystal (0.3 g): Fig 14. PXRD of
co-crystals of (R,S)3-[(1-phenyl cthylamino)-methyl]-hexanoic acid : (S)-1,1'-bi-2-
naphthol.

Example 21: Co-crystal formation of 5-Methyl-3-[((R)-1-phenyl-ethylamino)-
methyl]-hexanoic acid with (S)-1,1'-bi-2-naphthol
5-Methyl-3-[((R)-l-phenyl-ethylamino)-methyl]-hexanoic acid (0.2 g) is
dissolved in methanol (5 mL) and (S)-1,1'-bi-2-naphthol (0.25 g) is added to it at room
temperature. The mixture is stirred at 50 °C for 5 h. Reaction mixture is allowed to cool
to room temperature and kept over night, solvent is evaporated to obtain solid material.
PXRD analysis of obtained solid shows that it is amorphous in nature.

WE CLAIM:
1. A method of separation of the optically pure enantiomers of racemic (RS)-1,1'-bi-
2-naphthol of formula (1)

(i) reaction of racemic (RS)-1,1'-bi-2-naphthol of formula (I) with (S,S)-3-[(1-
phenylethylamino)-methyl]-hexanoic acid of the formula (II) or (R,R)-3-[(1-
phenylethylamino)-methyl]-hexanoic acid of formula (III)


to precipitate the first co-crystal of (S)-(-)-1,1'-bi-2-naphthol with (S,S)-3-[(1-
phenylethylamino)-methyl]-hexanoic acid or (R)-(+)-1,1'-bi-2-naphthol with (R,R)-3-
[(l-phenylethylamino)-methylJ-hexanoic acid in an alcoholic solvent.
(ii) clarification of the precipitate to isolate the first co-crystal of the step (i) and to
obtain a mother liquor,
(iii) decomposition of the co-crystal obtained in the step (i) with a Brønsted acid to
obtain the(S)-(-)-1,1'-bi-2-naphthol or (R)-(+ )-1,1'-bi-2-naphthol.
(iv) addition of either (R,R)-3-[(1-phenylethylamino)-methyl]-hexanoic acid or (S,S)
3-[(1-phenylethylamino)-methyl]-hexanoic acid to the mother liquor obtained in the
step (ii) to precipitate the second co-crystal of (R)-(+)-1,1'-bi-2-naphthol with (R,R)-
3-[(1-phenylethylamino)-methylJ-hexanoic acid or (S)-(-)-1,1'-bi-2-naphthol with
(S,S)-3-[(1-phenylethyllamino)-methyl]-hexanoic acid in an alcoholic solvent,
(v) clarification of the precipitate to isolate the second co-crystal of the step (iv). and
(vi) decomposition of the co-crystal obtained in the step (iv) with a Brønsted acid and
recovering the (R)-(+)-1,1'-bi-2-naphthol or (S)-(-)-1,1'-bi-2-naphthol.
2. A method of separation of the optically pure enantiomers of racemic (RS)-1,1'-bi-
2-naphthol of formula (I)


comprising the steps
(i) reaction of racemic (RS)-1,1'-bi-2-naphthol of formula (I) with (R,S)-3-[(1-
phenylethylamino)-methyl]-hexanoic acid of the formula (VI) or (S,R)-3-[(1-
phenylethylamino)-methyl]-hexanoic acid of formula (VII)

to precipitate the first co-crystal of (S)-(-)-1,1'-bi-2-naphthol with (R,S)-3-[(1-
phenylethylamino)-methyl]-hexanoic acid or (R)-(+)-1,1'-bi-2-naphthol with (S,R)-3-
[(1-phenylethylamino)-methyl]-hexanoic acid in an alcoholic solvent,
(ii) clarification of the precipitate to isolate the first co-crystal of the step (i) and to
obtain a mother liquor,
(iii) decomposition of the co-crystal obtained in the step (i) with a Brønsted acid to
obtain, the (S)-(-)-1,1'-bi-2-naphthol or (R)-(+)-1,1'-bi-2-naphthol,
(iv) addition of either (S,R)-3-[(1-phenylethylamino)-methyl]-hexanoic acid or (R,S)-
3-[(1-phenylethylamino)-rnethylJ-hexanoic acid to the mother liquor obtained in the
step (ii) to precipitate the second co-crystal of (R)-(+)-1,1'-bi-2-naphlhol with (S,R)-

3-[(1-phenylethylamino)-methyl]-hexanoic acid or (S)-(-)-1,1'-bi-2-naphthol with
(R,S)3-[(1-phenylethylamino)-methyl]-hexanoic acid in an alcoholic solvent.
(v) clarification of the precipitate to isolate the second co-crystal of the step (iv). and
(vi) decomposition of the co-crystal obtained in the step (iv) with a Brønsted acid and
recovering the (R)-(+)-1,1 '-bi-2-naphthol or (S)-(-)-1,1 '-bi-2-naphthol.
3. A method according to claim 1 or 2 wherein the optically pure enantiomers of
racemic (RS)-1,1'-bi-2-naphthol obtained at enantiomeric excess of at least 90%.
preferably at least 95%.
4. A method according to claim 1 or 2 wherein the alcoholic solvent of step (i) is
methanol.
5. A method according to claim 1 or 2 wherein the alcoholic solvent in the step (iii) is
methanol.
6. A method according to claim 1 or 2 wherein the reaction of the step (i) is carried
out at about 25-60° C, preferably at about 50° C.
7. A method according to claim 1 or 2 wherein the reaction of the step (iii) is carried
out at about 25-60° C, preferably at about 50° C.

8. A method according to claim 1 wherein the molar ratio of (S,S)-3-[(1-
phenylethylamino)-methyl ]-hexanoic acid or (R,R)-3-[(1 -phenylethylamino)-methyl]-
hexanoic acid to racemic (RS)-1,1'-bi-2-naphfhol is 0.5 to 1.5. preferably 0.5.
9. A method according to claim 2 wherein the molar ratio of (R,S)-3-[(1-
phenylethylamino)-methyl ]-hexanoic acid or (S, R)-3-[(1 -phenylethylamino)-methyl ]-
hexanoic acid to racemic (RS)-1,1'-bi-2-naphthol is 0.5 to 1.5. preferably 0.5.

10. A method according to claim 1 and 2 wherein the Bransted acid used in steps (i)
and (iii) is selected from hydrochloric acid, sulfuric acid and acetic acid.
11. A method according to claim 10 wherein the Bransted acid used in steps (i) and
(iii) is provided as a biphasic mixture with an organic solvent immiscible with water,
preferably ethyl acetate.
12. A co-crystal (S,S)-3-[(1-phenylethylamino)-methyl]-hexanoic acid : (S)-(-)-1,1'-
bi-2-naphthol of the formula (IV)

characterized by the powder X-ray diffraction peaks at the 2-theta values 9.36. 10.33.
12.17, 15.53.17.53, 17.87, 17.96, 20.38, 21.76, 22.52, 24.47 and 27.76.
13. A co-crystal according to claim 12 further characterized by differential scanning
calorimetry peak at about 185° C.
14. A co-crystal according to claim 12 further characterized by specific optical
rotation angle at about (-) 15.71 °.

15. A co-crystal according to claim 12 further characterized by the IR stretching
peaks at about cm-1 3449. 3059, 2960, 2458, 1620. 1595. 1557. 1504. 1458, 1431.
1397, 1324. 1307. 1275. 1139, 1123, 818, 750 and 709.
16. A co-crystal according to any of the claims 12-15 wherein the composition of
(S,S)-3-[(1-phenylethylamino)-methyl)-hexanoic acid and (S)-(-)-1,1'-bi-2-naphthol is
1:1.
17. A co-crystal (R,R)-3-f(1-phenylethylamino)-melhyl]-hexanoic acid : (R)-(+)-1,1'-
bi-2-naphthol of the formula (V)

characterized by the powder X-ray diffraction peaks at the 2-theta values 9.34. 10.35.
12.18. 15.51. 15.66, 17.04, 17.55, 17.86. 18.24, 18.67, 19.19, 20.37. 20.62. 21.54.
21.76, 22.54, 23.55. 24.53 and 27.24.
18. A co-crystal according to claim 17 further characterized by differential scanning
calorimetry peak at about 186° C.
19. A co-crystal according to claim 17 further characterized by specific optical
rotation angle at about (+) 16.44°.

20. A co-crystal according to claim 17 further characterized by the IR stretching
peaks at about cm-1 3449. 3059. 2960, 2458. 1620, 1595. 1557. 1504. 1458. 1431.
1397, 1324. 1307. 1275, 1139. 1123, 818, 750 and 709.
21. A co-crystal according to any of the claims 17-20 wherein the composition of
(R,R)-3-[(1-phenylethylamino)-methyl]-hexanoic acid and (R)-(+)-1,1'-bi-2-naphthol
is 1:1.
22. A co-crystal (R,S)-3-[(1-phenylethylamino)-methylJ-hexanoic acid : (S)-(-)-1,1'-
bi-2-naphthol of the formula (VIII)

characterized by the powder X-ray diffraction peaks at the 2-theta values 9.38. 10.35,
12.23. 15.44. 15.51, 17.60. 17.87. 19.30. 20.45, 21.66. 22.57, 24.41. 24.69 and 28.48.
23. A co-crystal according to claim 22 further characterized by differential scanning
calorimetry peak at about 177° C.
24. A co-crystal according to claim 22 further characterized by specific optical
rotation angle at about (-)l 8.46°.

25. A co-crystal according to claim 22 further characterized by the IR stretching
peaks at about cm-1 3449, 3059, 2960, 2458. 1620. 1595. 1557, 1504. 1458. 1431.
1397, 1324, 1307. 1275, 1139, 1123. 818, 750 and 709.
26. A co-crystal according to any of the claims 22-25 wherein the composition of
(R,S)-3-[(1-phenylethylamino)-methylJ-hexanoic acid and (S)(-)-1,1'-bi-2-naphthol
is 1:1.
27. A co-crystal (S,R)-3-[(1-phenylethylamino)-methyl]-hexanoic acid : (R)-(+)-1.1'-
bi-2-naphthol of the formula (IX)

characterized by the powder X-ray diffraction peaks at the 2-thcta values 9.25. 10.31.
12.23, 15.44. 15.51, 17.60, 17.87, 19.30, 20.45, 21.66, 22.57, 24.41. 24.69 and 28.48.
28. A co-crystal according to claim 27 further characterized by differential scanning
calorimetry peak at about 172° C.
29. A co-crystal according to claim 27 further characterized by specific optical
rotation angle at about (+) 19.97°.

30. A co-crystal according to claim 27 further characterized by the IR stretching
peaks at about cm-1 3449, 3059, 2960. 2458, 1620. 1595, 1557, 1504. 1458. 1431.
1397, 1324. 1307, 1275, 1139. 1123, 818, 750 and 709.
31. A co-crystal according to any of the claims 27-30 wherein the composition of
(S,R)-3-[(1-phenylethylamino)-methyl]-hexanoic acid and (R)-(+)-1,1'-bi-2-naphthol
is 1:1.
32. A co-crystal of diastereomeric mixture of compound [XVII] and IXVIII] 5-
melhyl-3-[((R-1-phenyl-ethylamino)-methyl]-hexanoic acid with : (R)-(+)-1,1'-bi-2-
naphthol is characterized by the powder X-ray diffraction peaks at the 2-theta values
8.20.9.01, 10.18. 11,95, 13.00, 15.24, 17.32, 18.19, 18.62. 19,12, 19.89,20.55.21.00,
22.21,25.35. 25.85 and 37.26

Novel method for synthesis of optically pure (S)-(-)-1,1'-bi-2-naphthol and/or (R)-
(+)-1,1'-bi-2-naphthol via resolution of racemic (RS)-1,1'-bi-2-naphthol through
formation of co-crystal with optically active derivatives of γ -amino acids.