METHOD OF RESOLUTION OF (RS) - 1 , 1 ' - Bl - 2 - NAPHTHOL FOR OBTAINING ENANTIOMERIC PURE
I.E. (S) - (-) " 1 , 1 ' "Bl - 2 -NAPHTHOL AND/OR (R) - ( ) - 1 , 1 ' - Bl - 2 - NAPHTHOL VIA CO - CRYSTAL
FORMATION WITH OPTICALLY ACTIVE DERIVATIVES OF GAMMA -AMINO ACIDS
Field of Invention:
The invention relates to novel method for synthesis of optically pure ($-(-)- l,l'-bi-2-
naphthol and/or (#)-(+)- l,l'-bi-2-naphthol via resolution of racemic (i?5)-l , -bi-2-naphthol
through formation of co-crystal with optically active derivatives of g -amino acids.
Background of the Invention:
U'-bi-2-naphthol [CAS. No 602-09-05] [I] is one of the industrially important
chemicals and is produced in large quantities all over the world.
l,l'-bi-2-naphthol occurs in two optically active forms because of its restricted
rotation viz. (S)-{-)- , 1'-bi-2-naphthol [CAS No. 18531-99-2] and (£)-(+)- l,l'-bi-2-naphthol
[CAS No. 18531-94-7].
(S^-(-)-l,l '-bi-2-naphthol and (i?)-(+)-l,l'-bi-2-naphthol are generally obtained by
resolution of racemic i.e. (J?¾)-l,l'-bi -2-naphthol, which is synthesized by oxidative coupling
of 2-naphthol in presence of transition metal salts having variable valence such as FeCl3,
CuS0 4, CuCl2,VO complex, etc. (J. Org. Chem. 1989, 54, 1252)
Both the optically pure (5>(-)-l , -bi-2-naphthol and (i?)-(+)-l,l'-bi-2-naphthol have
wide applications in synthetic chemistry and are used as building blocks for the
synthesis/manufacture of many important chemicals including natural products, (Tetrahedron
1995, 51, 9353; Tetrahedron 2000, 56, 2325); and also as chiral auxiliaries in stoichiometric
quantity as well a s in catalytic amount in various asymmetric syntheses.
The optically pure ($-(-)- l,T-bi-2-naphthol and (i?)-(+)-l,T-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 ,r-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 ( - l ,r-bi-2-naphthol has been
extensively studied with essentially two major approaches such a s 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. So , 1989, 1 1 1, 4953)
Enantioselective trans-esterification reaction of vac- 1-indanol with rac- I , -
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) - l -bi-2-naphthoI 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)-l,l'-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 (i?5)-l,l'-bi-2-naphthol has also reported low
enantiomeric excess. The reported method needs an additional step for preparation of
binaphthol 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 l,l'-bi-2-naphthol through enzymatic
resolution is very high. Although, commercially available enzymes such as lipases are used
for enantioselective hydrolysis of l,l'-bi-2-naphthol ester, enantiomeric excess is far from
desirable.
Asymmetric oxidative coupling i s scientifically interesting and demonstrated by using
Camellia sinensis cell culture or horseradish peroxidase. However, enantiomeric excess i s far
from satisfactory (Tetrahedron Lett. 2002, 43, 8499; Tetrahedron Lett. 1997, 38, 5695)
II) Chemical resolution:
Resolution of (i? )- l , l ' -b i-2-n ap hthol via formation of diastereomeric inclusion
complexes with various chiral hosts i s very well documented. Some of these methods
reportedly gave low enantiomeric 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
(i?5)-l,l'-bi-2-naphthol. In the said method, synthesis of chiral amide derivatives is tedious
and requires POCl . Furthermore to obtain optically pure l,l'-bi-2-naphthol from complex
needs an additional step of forming complex with aqueous NH NH2 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)-l, l'-bi-2-naphthol via
amide derivatives of tartaric acid.
Resolution of (i?S)-l,l'-bi-2-naphthol by forming inclusion complex with chiral
cinchonidium halides 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 7 -tolyl methyl sulfoxide (Tetrahedron Lett. 1984,
25, 4929-4932) are not at all cost effective processes at industrial scale.
Resolution of (i?S -l ,l '-bi-2-naphthol by forming inclusion complex with Z-proline
(Tetrahedron: Asymmetry, 1995, 6, 341-344); (¾)-(a)-methyl benzylamine (J. Org. Chem.
1999, 64, 7643-7645); (i?)-2-aminobutanol (Synthesis 1990, 3, 222-223); (S)-5-
oxopyrrolidine-2-carboxanilide (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 l,l'-bi-2-
naphthol.
Resolution of (i ?S - l , -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, 1 1 1-114) 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 l,l'-bi-2-naphtliol.
Moreover, cost per unit kg of final product is also high. Figure 2 gives the schematic
representation of resolution of 7 -l , -bi-2-naphthol via (i^-menthyl chloroformate.
(Ill) Formation of phosphate ester diastereomeric inclusion complexes: Resolution of
(i?5)-l,l'-bi-2-naphthol is also demonstrated by forming phosphate ester of (RS)-l,V-bi-2-
naphthol followed by diastereomeric complex with optically pure a-methylbenzylamine (J.
Org. Chem. 1995, 60, 7364-7365) or Z-menthol (J. Org. Chem. 1993, 58, 7313-7314), which
is further separated by crystallization. Above said methods use LiAlH which is not
environmentally benign and require special handling conditions. Hence it cannot be used as
an industrial process for obtaining optically pure l,l'-bi-2-naphthol. Fig. 3. gives the
schematic representation of resolution of (i?5)-l,l'-bi-2-naphthol via phosphate ester
diastereomeric complex with chiral a-methyl benzyl amine.
IV) Formation of borate ester diastereomeric inclusion complexes: Resolution of (RS)-
l,l -bi-2-naphthol is also demonstrated by forming borate ester of (i - l l'~bi~2-naphthol
and further treating with (i?)-a-methylbenzylamine (J. Org. Chem. 1999, 64, 7643-7645);
quinine (CN 1097728); TMEDA (Tetrahedron: Asymmetry 1996, 7, 2471-2474) or Z-Proline
to obtain diastereomeric complex (Tetrahedron: Asymmetry 1998, 9, 3985), 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 (i? - l , -bi-2-naphthol via borate ester
complex.
(V) Conglomerate separation: Toda et ah, 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 (i?S)-l,l'-bi -2-naphthol by forming
inclusion complex with N-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 of 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 naphthyletliyl
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, l'-bi-2-naphthol and (R)-(+)-l, l'-bi-2-naphthol.
This invention provides that.
Summary of Invention:
The present invention is directed towards the method for preparation of
enantiomerically pure ($-(-)-l,l'-bi-2-naphthol and (i?)-(+)-l,l'-bi-2-naphthol from (RSJl,
l'-bi-2-naphthol (I) through formation of co-crystal with sequential addition of desired
optically pure g -amino acid derivatives.
S)- l ,r-bi-2-naphthol
-methyl]-hexanoic acid -met y - exano c ac (R) +) l,l'-bi-2-naphthol
RS - l,l '-bi-2-naphthol
MeOH (7?,5)-3-[(l-phenyl
50 °C ethylamino)
-methyl]-hexanoic acid
(R,S)-3 -[( 1-phenyl ethylamino)-methyl]-
Solution (enriched with {¾)-(+)- l ,l'-bi-2-naphthol)
hexanoic acid: ( -(-) - l , l '-bi-2-naphthol
(Precipitate) (S,i?)-3-[(l-phenyl
' IN HC1 MeOH ethylamino)
EtOAc 50 C -methyl] -hexanoic acid
(S,/?)-3-[(l-phenyl ethylamino)-methyl]-
hexanoic acid: ) -(+)- , l'-bi-2-naphthol (Precipitate)
-y 1N HC1
EtOAc
l,l '-bi-2-naphthol
(R,S)-3-[(l-phenyl (S,/?)-3-[(l-phenyl
ethylamino) ethylamino)
-methyl]-hexanoic acid -methyl] -hexanoic acid (R - +) l,l '-bi-2-naphthol
Co-crystal is defined as a crystal that contains two different molecules as a complex
held together by H-bonds, p-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 Engg. 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
diastereomer of 3-[(l -phenyl ethylamino)-methyl] -hexanoic acid to a mixture of racemic
(i?5)-l,l'-bi-2-naphthol [I] in methanol, wherein only one form of enantiomerically pure 1,1 ' -
bi-2-naphthol forms a 1:1 co-crystal with the said optically pure g-amino acid derivative. The
co-crystal thus formed crystallizes out leaving the other antipode of l,l'-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, decantation etc.
The mother liquor, which contains the other antipode of l,l'-bi-2-naphthol, is treated
with the other antipode of optically pure g-amino acid derivative to form a similar 1:1 cocrystal.
The co-crystal is then decomposed with a hydrogen ion source like a Bransted acid
such as dilute hydrochloric acid, dilute sulfuric acid, acetic acid etc. to obtain optically pure
l , -bi-2-naphthol. g -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 i? l , -bi-2-naphthol [I] is reacted with ( S -3-[(l -phenyl ethylamino)-
methyl]-hexanoic acid [II],
there is formation of the easily separable co-crystal with ($-(-)- l -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-[(l -phenyl ethylamino)
hexanoic acid [III],
[HI]
which forms the easily separable co-crystal with (i?)-(+)-l,l'-bi-2-naphthol and is
separated by filtration.
The co-crystals thus obtained i.e. (S,S)-3-[(l -phenyl ethylamino)-methyl]-hexanoic
acid: (^-(-)-l,l'-bi-2-naphthol [IV] and (R,R)-3-[(\ -phenyl ethylamino)-methyl]-hexanoic
acid: (i -(+)-l , -bi-2-naphthol [V] are treated separately with dilute hydrochloric acid to
obtain (S) and R) optically pure l,l'-bi-2-naphthol respectively. The % ee of the (R)-(+)-l,Vbi-
2-naphthol and ($-(-)- l,l'-bi-2-naphthol have been found to be min of 99 %.
[IV]
[V]
Single crystal X-ray diffraction pattern analysis of co-crystal ((+)-l,l'-bi-2-naphthol in the mother
liquor.
Further, mother liquor (filtrate) is reacted with ( ' i?)-3-[(l -phenyl ethylamino)-
methyl]-hexanoic acid [VII],
[VII]
which forms the easily separable co-crystal with (7?j-(+)-l,l'-bi-2-naphthol and is
separated by filtration.
The co-crystals thus obtained i.e. (i?,S)-3-[(l-phenyl ethylamino)-methyl]-hexanoic
acid: (S>(->l,l'-bi-2-naphthol [VIII] & (^^-[(l-phenyl ethylamino)-methyl]-hexanoic
acid: (i^-(+)-l,l'-bi-2-naphthol [IX] are treated with dilute hydrochloric acid to obtain (S)-(-
)-l ,r-bi-2-naphthol and (7?>(+)-l,l'-bi-2-naphthol respectively. The % ee of the (R)-(+)-l,V-
-2-naphtho and ($-(-)- l ,r-bi-2-naphthol have been found to be min of 95 %.
(VIII)
(IX)
Single crystal X-ray diffraction pattern analysis of co-crystal (R,S)-3-[(l -phenyl ethylamino)-
methyl] -hexanoic acid: ($-(-)- l,l'-bi -2-naphthol V shows that the composition is 1:1.
Brief Description of Accompanying drawings
Figure 1: Schematic representation of resolution of (7?5^-l,l'-bi-2-naphthol via amide
derivatives of tartaric acid
Figure 2 : Schematic representation of resolution of - l , -bi-2-naphthol via (R)-
menthyl chloroformate
Figure 3: Schematic representation of resolution of (i? S}-l , -bi-2-naphthol via
phosphate ester diastereomeric complex with chiral ¾-methyl benzyl amine
Figure 4. Schematic representation of the resolution of (i -l , -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-[(l-phenyl ethylamino)-methyl] -hexanoic
acid : ( -l ,r-bi-2-naphthol [VI]
Figure 11: PXRD of co-crystal of (i?,>S)-3-[(l-phenyl ethylamino)-methyl]-hexanoic
acid : (S)- l,l '-bi-2-naphthol [VIII]
Figure 12: PXRD of co-crystal of (i?,i?J-3-[(l-phenyl ethylaniino)-methyl]-hexanoic
acid : ( - l ,l '-bi~2-naphthol [V]
Figure 13: PXRD of co-crystal of (S,R)~3-[(\ -phenyl ethylamino)-methyl]-hexanoic
acid : (i l ,l '-bi-2-naphthol [IX]
Figure 14: PXRD of co-crystal of 5-methyl-3-[((i?)-l-phenyl-ethylamino)-methyl]-
hexanoic acid: (i?J-l,l'-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 [I] to
corresponding optically pure enantiomer is obtained via formation of co-crystal with
substituted g -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 Aand Qrange 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 cocrystal
[IV] is given in figure 5.
IS
Table 1. Crystal data and structure refinement of [II] and SJ-(-j-l,l'-bi-2-naphthol:
co-crystal [IV]
Empirical formula C3 H3 0
Formula weight 535.66
Temperature 293(2) K
Wavelength 0.71073 A
Crystal system Orthorhombic
Space group P212121
Unit cell dimensions a = 10.1158(18) A alpha = 90 deg.
b = 11.293 (2) A beta 90 deg.
c = 26. 8(5) A gamma = 90 deg
Volume 2983.8(9) A
Z 4
Density (calculated) 1.192 g
Absorption coefficient 0.077 mm 1
F(000) 1144
Crystal size 0.44 x 0.40 x 0.28 mm
Theta range for data collection 1.56 to 28.40 deg.
Index ranges -10<=h<=12, -15<=k<=14, -33<=1<=34
Reflections collected 17943
Independent reflections 6929 [R(int) 0.0313]
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.9787 and 0.9669
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 6929 / 0 / 365
Goodness-of-fit on F 2 1.1 13
Final R indices [I>2sigma(I)] Ri = 0.0702, wR2 0.1513
R indices (all data) Ri = 0.0896, wR2 = 0.1612
Absolute structure parameter -0.4(15)
Largest diff. peak and hole 0.368 and -0.171 e.A
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
Flack 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 g-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
NMR data and FTIR of g - amino acid confirm the above structure, i.e. Carbon atom 1 and
2 of (VII) are both in 'S' configuration.
FTIR (K - pellets): 2960, 1623, 1547 cm- 1;
1H NMR (CDCI3, 200 MHz): d 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, 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 (EI): Ci5H23N0 2: 249.17; [M+H]+: 250.20
The sodium salt of compounds [II], [III], [VI] and [VII] show an R band at 1730 cm
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
phenyl ethylamino)-methyl]-hexanoic acid:(SJ-(-)-l,l'-bi-2-naphthol is same as powder Xray
diffraction data obtained from bulk material.
Crystal structure of the single crystal of the co-crystal [VIII] is measured on Bruker
Smart Apex CCD diffractometer having software SHELXTL-PLUS at temperature 293 (2) K
and wavelength 0.71073 A and Q range for data collection is 1.56 to 28.40°. Table 2
summarizes the crystal data and structure refinement and ORTEP diagram of the single
crystal of co-crystal [VIII] is given in figure 6.
Table 2. Crystal data and structure refinement of [VI] and ¾ - 9-l,l'-bi-2-naphthol:
co-crystal [VIII]
Empirical formula C3 H37 0
Formula weight 535.66
Temperature 293(2)
Wavelength 0.71073 A
Crystal system Orthorhombic
Space group P212121
Unit cell dimensions a = 10.039 A alpha = 90 deg.
b = 11.18 A beta = 90 deg.
c = 26.35 A gamma = 90 deg
Volume 2958.132
Z 4
Density (calculated) 1.2 g/cm"
Absorption coefficient 0.077 mm 1
F(000) 1144
Crystal size 0.44 x 0.40 x 0.28 mm
Theta range for data collection 1.56 to 26.290 deg.
R indices (all data) Ri = 0.0648, wR = 0.1944
The said optically pure g -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 g -amino acids" and described hereinafter.
5-hydiOxy-4-n-propyl-5H-furan-2-one [XIa] when reacted with (,S)-(a)-methyl benzyl
amine [XII] gives the compound [XIII]. Hydrogenation of compound [XIII] in wo-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-/?-propyl-5H-furan-2-one [XIa] when reacted with (i?)-(a)-methyl benzyl
amine [XIV] gives the compound [XV]. Hydrogenation of compound [XIII] in wo-propanol
gives the diastereomeric compounds [III] and [VII], which are 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-hydiOxy-4-/iO-butyl-5H-furan-2-one [Xlb] when reacted with (i?)-(a)-methyl
benzyl amine [XIV] gives the compound [XVI]. Hydrogenation of compound [XVI] in isopropanol
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
Table 3 : Physical Properties of compounds [II], [III], [VI] and [VII]
Compound [II] with (6)-l,l'-bi-naphthol gives the co-crystal (.S,.S)-3-[(l -phenyl
ethylamino) -methyl] -hexanoic acid: ($-(-)- l,l'-bi-2-naphthol [IV] and compound [VI] with
(SH-)-l,l'-bi-naphthol iyes (i?,5)-3-[(l-phenylethylamino)-methyl]-hexanoic acid: ($-(-)-
l,r-bi-2-naphthol [VIII].
Compound [III] with (7?)-l,l'-bi-naphthol gives the co-crystal (R,R)-3-[(l -phenyl
ethylamino) -methyl] -hexanoic acid: (i )-(+)-l,l'-bi-2-naphthol [V] and compound [VII] with
(i?)-(+)~l , -bi-naphthol gives the co-crystal (5'R)-3-[(l-phenylethylamino)-methyl]-
hexanoic acid: (Rj-(+)-l,l'-bi-2-naphthol [IX].
Physical properties of co-crystals [IV], [V] [VIII] and [IX] are summarized in Table 4.
5
Table 4 : Physical properties of co-crystals [IV], [V] [VIII] and [IX]
(¾S)-3-[(l-phenyl 177.69 (-) 18.46 9.38, 10.35, 12.23, 3449, 3059, 2960,
ethylamino)-methyl] - 15.44, 15.51, 17.60, 2458, 1620, 1595,
hexanoic acid : -(-)- 17.87, 19.30, 20.45, 1557, 1504, 1458,
l ,r-bi-2-naphthol [VIII] 21.66, 22.57, 24.41, 1431, 1397, 1324,
24.69 and 28.48 1307, 1275, 1139,
1123, 818, 750, 709
( ,R)~3-[(l-phenyl 172.62 (+) 19.97 9.25, 10.31, 12.23, 3449, 3059, 2960,
ethylamino)-methyl] - 15.44, 15.51, 17.60, 2458, 1620, 1595,
hexanoic acid : (R)-(+)- 17.87, 19.30, 20.45, 1557, 1504, 1458,
l ,r-bi-2-naphthol [IX] 21.66, 22.57, 24.41, 1431, 1397, 1324,
24.69 and 28.48 1307, 1275, 1139,
1123, 18, 750, 709
Table 5 gives the comparative data of FTIR spectra of free racemic (RS)-I, V-bi-2-
naphthol [I], co-crystal ethylamino)-methyl] -hexanoic acid :(S)-(-)-l,Vbi-
2-naphthol] [IV] and ( - - l -phenyl ethylamino)-methyl] -hexanoic acid [II].
Table 5 : FTIR spectral data of Compound [I], [II] and [IV]
Co-crystal of (5",5)-3-[(l- (i?5)-l,l' bi-2-naphthol ( -[(l - he l ethylamino)-
phenyl ethylamino)- [I] * (cm 1) methyl]-hexanoic acid [II]*
methyl]-hexanoic acid & (cm 1)
(S>(-)-l,l'-bi-2-naphthol
[IV] * (cm-
3449, 3059, 2960, 2458, 3486, 3402, 1617, 1596, 3444, 2960, 1623, 1547, 1497,
1620, 1595, 1557, 1504, 1510, 1461, 1470, 1381, 1397, 703
1458, 1431, 1397, 1324, 1217, 1174, 1146, 826,
1307, 1275, 1139, 1123, 751, 573
818, 750, 709
*FTIR absorption peak observed by preparing pellet of solid of respective compound
dispersed in dry potassium bromide.
Surprisingly it is observed that compound [III] and compound [VII] are
diastereomers, where the stereo-configuration at benzylic center is same i.e. "i?". When these
compounds are reacted with (i?)-(+)- 1,1 '-bi-naphthol, they give the co-crystals [V] and [IX]
respectively. Similarly it is also observed that compound [II] and [VI] are diastereomers,
where the stereo-configuration at benzylic center is same i.e. When these compounds are
reacted with 1,1' -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-methyl-3-[((i?)-l-phenyl-ethylamino)-
methyl]-hexanoic acid i.e. the diastereomeric mixture of compounds [XVII] and [XVIII].
When the mixture is treated with (i?)-(+)- 1,1' -bi-naphthol it gives the co-crystal 5-methyl-3-
[((i?)-l-phenyl-ethylamino)-methyl]-hexanoic acid : 1,1' -bi-naphthol, which
precipitates out from the reaction media and similarly when diastereomeric mixture of
compounds [XVII] and [XVIII] is treated with (£)-(-)- I ,G -bi-naphthol it remains dissolved in
reaction media. Hence it could be a method for resolution of (RS)-l,l '-bi-naphthol to obtain
optically pure (S) or (R)- 1,1 '-bi-naphthol.
. Powder x-ray diffraction pattern for co-crystal 5-methyl-3-[((i?)-l-phenylethylamino)-
methyl]-hexanoic acid (diastereomeric mixture of compound [XVII] and
[XVIII]): (£)-(+)- 1,1 '-bi-naphthol is given in Figure 14.
In all cases, the co-crystal formation of the optically active g-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 g-amino
acids is carried out at a temperature range of 25-60° C, preferably at 50° C.
Molar ratio of optically pure g-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 g-amino acids are decomposed
in a biphasic mixture of ethyl acetate: dilute hydrochloric acid (1:1) at room temperature.
The optically active g -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 6.0.1.
Analytical Methods:
The enantiomeric excess (ee) is determined by HPLC using a Shimadzu LC 2010
system equipped with a chiral column (Chiral pale IA, 4.6mm x 250mm, 5mhi), column oven
temperature 40 °C and UV visible detector (230 nm). Mobile phase is n-hexane (94) nbutanol
(5) : ethanol (1): Trifluoacetic acid (0.3 mL) with flow rate 1 mL , injection volume
20 m. . NMR spectra are obtained at 200 and 400 MHz Brulcer instruments, with CDC13 as
solvent. Chemical shifts (d) a e given in ppm relative to tetramethylsilane d = 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
°C/min and endothermic peak is recorded in 0C and DH is reported in J/g.
Example 1: Synthesis of 5-hydroxy-4-/i-propyl-5 H-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-z' -propy ether is added to the aqueous phase. The organic phase is removed and
the aqueous phase further extracted with di-z' -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-5 H-furan-2-one are obtained as light brown oil.
FTIR (neat): 3367, 1735 cm"1.
1H NMR (CDC1 , 200 MHz): d 0.93-1.00 (t, 3H), 1.56-1.67 (q, 2H), 2.31-2.43 (q, 2H), 5.81 (s,
1H), 6.02 (s, 1H).
MS (EI): C H 0O3: 142.06; [M+H]+: 142.93.
Example 2: Synthesis of 5-hydroxy-l -[(SJ-phenyl-ethyl]-4-«-propyl-l,5-dihydro-pyrrol-2-
one [XIII]
5-hydroxy-4 - -propyl-5 H-furan-2-one (10.0 g) is dissolved in wo-propanol (100 mL) and
(5 - -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-l-[(.S )-phenyl-ethyl]-4-n-propyl-l,5-dihydro-pyrrol-2-one as dark yellow oil (16.5 g).
FTIR (neat): 3321, 1749, 1165 cm 1 .
1H NMR (CDC13, 200 MHz): d 0.86-0.94 (t, 3H), 1.31-1.37 (t, 3H), 1.43-1.57 ( , 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): C5H19NO2: 245.14; [M+H : 246.51.
Example 3 : Synthesis of 5-hydroxy-l -[(R)-phenyl-ethyl]-4-«-propyl-l,5-dihydro-pyrrol-2-
one [XV]
5-hydroxy-4-«-propyl-5 H-furan-2-one (10.0 g) is dissolved in / -propano (100 L) and
(i?)-a-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-l-[(i? )-phenyl-ethyl]-4-n-propyl-l,5-dihydro-pyrrol-2-one as dark yellow oil (16.5 g).
FTIR (neat): 3321, 1749, 1165 cm 1 .
1H NMR (CDCI3, 200 MHz): d 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): 5H 9 O2: 245.14; [M+H]+: 246.51.
Example 4 : Hydrogenation of 5-hydroxy-l -[(Sj-phenyl-ethyl]-4-/?-propyl-l,5-dihydropyrrol-
2-one [XHIJwith Pd/C
5-hydroxy-l -[(Sj-phenyl-ethyl]-4-n-propyl-l,5-dihydro-pyiTol-2-one (16.5 g) is
dissolved in z'so-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; (S,S)-3-[(l -phenyl ethylamino)-methyl]-
hexanoic acid precipitates out from the reaction media and R,S - -[ -phenyl ethylamino)-
methylj-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-[(l -phenyl ethylamino)-
methylj-hexanoic acid as a off-white solid obtained after vacuum filtration.
Filtered cake contains Pd/C and (5',5)-3-[(l -phenyl ethylamino)-methyl]-hexanoic
acid which is suspended in 50 ml methanol and stirred for 20 min to dissolve ( , )-3- [(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-[(l -phenyl ethylamino)-methyl]-
hexanoic acid as a white solid.
(S,S)-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid [II]:
FTIR (KBr pellets): 2960, 1623, 1547 cm 1;
1H NMR (CDC13, 200 MHz): d 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, 2H), 2.75-2.78 (d, IH), 4.12-4.17 (q, IH), 7.35-
7.42 (m, 3H), 7.47-7.51 (m, 2H); MS (EI): Ci5H23N0 2 249.17; [M+H]+: 250.20
DSC (10 °C/min): Peak at 147.16°C
(R,S )-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid [VI]:
FTIR (KBr pellets): 2956, 1619, 1549, 1400 cm 1;
NMR (CDCI3, 200 MHz): d 0.76-0.79 (t, 3H), 1.14-1.23 (m,4H), 1.66-1.68 (d, 3H), 2.26-
2.30 ( , 2H), 2.53-2.59 (t, 2H), 2.77-2.80 (d, IH), 4.06-4.11 (q, IH), 7.31-7.57 (m, 5H);
MS (EI): C15H23N0 2: 249.17; [M+H]+: 250.05.
DSC (10 °C/min): Peak at 120.1°C
Example 5 : Hydrogenation of 5-hydroxy-l-[(i?>phenyl-ethyl]-4-n-propyl-l,5-dihydropyrrol-
2-one [IX] with Pd/C
5-hydroxy- 1-[(R) -phenyl-ethyl] -4-rc-propyl-1,5-dihydro-pyrrol-2-one (16.5 g)
is dissolved in O-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 stalling
material, the reaction is stopped. In the reaction, diastereomers separate; (R,R)-3-[(l -phenyl
ethylamino)-methyl]-hexanoic acid precipitates out from the reaction media and (5',i?)-3-[(lphenyl
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 6.0 g of (S,R)-3-[(l -phenyl ethylamino)-
methylj-hexanoic acid as a off-white solid obtained after vacuum filtration.
Filtered cake, which contains Pd/C and (i?,i?)-3-[(l -phenyl ethylamino)-methyl]-
hexanoic acid is suspended in 50 ml methanol and stirred for 20 min to dissolve (R,R)-3-[(lphenyl
ethylamino)-methyl]-hexanoic acid. Pd/C is separated by filtration. Filtrate is
concentrated under vacuum to obtain 8.0 g of (i?,i?)-3-[(l -phenyl ethylamino)-methyl]-
hexanoic acid as white solid.
(i?,R)-3-[(l-phenyl ethyIamino)-methyl]-hexanoic acid [HI]:
FTIR (KBr pellets): 2958, 1621, 1548, 1397 cm 1 .
1H NMR (CDC13, 200 MHz): d 0.80-0.87 (t, 3H), 1.17-1.22 (m, 4H), 1.67-1.70 (d, 3H),
2.13-2.19 (d, 2H), 2.44-2.61 (t, 2H), 2.74-2.80 (d, IH), 4.11-4.20 (q, IH), 7.30-7.54 (m, 5H).
MS (EI): C 5H23N0 2: 249.17; [M+H]+: 250.03.
DSC (10 °C/min): Peak at 148.11 °C
S ,R)-3-[(l-phenyI ethyIamino)-methyI]-hexanoic acid [VII]:
FTIR (KBr pellets): 2957, 1620, 1550, 1399 cm 1 .
H NMR (CDCI3, 200 MHz): d 0.75-0.81 (t, 3H), 1.18-1.41 (m, 4H), 1.65-1.69 (d, 3H),
2.20-2.33 (m, 2H), 2.49-2.60 (t, 2H), 2.76-2.82 (d, IH), 4.07-4.17 (q, IH), 7.32-7.54 (m, 5H).
MS (EI): Ci5H23N0 2: 249.17; [M+H : 250.50.
DSC (10 °C/min): Peak at 119.3°C
Example 6: Diastereomeric co-crystal formation of (S ,5)-3-[(l-phenyl ethylamino)-
methyl]-hexanoic acid with (S)-l,l'-bi-2-naphthol
(5,5)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid (1.0 g) is dissolved in
methanol (20 mL) and (5)-l,l'-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 ( - - l -
phenyl ethylamino)-methyl]-hexanoic acid : (S )-l,l'-bi-2-naphthol [VI]
DSC (10 °C/min): Peak at 185.82 °C.
Example 7: Diastereomeric co-crystal formation of (S,S )-3-[(l-phenyl ethylamino)-
methyLJ-hexanoic acid with (R)-l,l'-bi-2-naphthol
(5',S)-3-[(l -phenyl ethylamino)-methyi] -hexanoic acid (1.0 g) is dissolved in methanol
(20 mL) and (i?)-l,r-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 (i ?,S)-3-[(l-phenyl ethylamino)-
methyl]-hexanoic acid with (S)-l,l'-bi-2-naphthol
(i?,5)-3-[(l -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 (i?,5)-3-[(lphenyl
ethylamino)-methyl]-hexanoic acid : (S)-l,l'-bi-2-naphthol [VIII].
DSC (10 °C/min): Peak at 77.69 °C.
Example 9 : Diastereomeric co-crystal formation of (R,S )-3-[(l-phenyl ethylamino)-
methyl]-hexanoic acid with (R)-l,l'-bi-2-naphthol
(i?,5)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid (1.0 g) is dissolved in
methanol (20 mL) and (i?)-l,l'-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-[(l-phenyl ethylamino)-
methylj-hexanoic acid with (R -1,1'-bi-2-naphthol
(i J ?)-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid (1.0 g) is dissolved in
methanol (20 mL) and (i?)-l,l'-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-[(lphenyl
ethylamino)-methyl]-hexanoic acid : (i?)-l,l'-bi-2-naphthol [V].
DSC (10 °C/min): Peak at 186.71 °C
Example 11. Diastereomeric co-crystal formation of (R,R )-3-[(l -phenyl ethylamino)-
methyI]-hexanoic acid with (S)-l,l'-bi-2-naphthol
(i?,^)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid (1.0 g) is dissolved in
methanol (20 mL) and (5)-l,l'-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 ( ?,L)-3~[(1-r h I ethylamino)-
methylj-hexanoic acid with (if)-l,l'-bi-2-naphthol
( i?)-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid (1.0 g) is dissolved in
methanol (20 mL) and (i?)-l,l'-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)-methyl]-hexanoic acid : (i?J-l,r-bi-2-naphthol [IX].
DSC (10 °C/min): Peak at 172.62 °C.
Example 13. Diastereomeric co-crystal of (S,R )-3-[(l-phenyl ethylamino)-methyl]-
hexanoic acid with (S)-l,l'-bi-2-naphthol
(i?,i?)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid (1.0 g) is dissolved in
methanol (20 mL) and (5)-l,l'-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)-l,l'-bi-2-naphthol from (RS)-l,l'-bi-2-naphthol via
formation of diastereomeric co-crystal with (S,S)-3-[(l-phenyl ethylamino)-methyl)-
hexanoic acid.
( , -3-[(l -phenyl ethylamino)-methyl]-hexanoic acid (5.0 g) is dissolved in
methanol (20 mL) and (i¾)-l,r-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 IN 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)-l,l '-bi-2-naphthol ( 1.5 g) having 99 % ee.
The acid aqueous solution which contains hydrochloride salt of (5',S)-3-[(l -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 (S)-l,l'-bi-2-naphthol from (RS)-l,l'-bi-2-naphthol via
formation of diastereomeric co-crystal with (R,S )-3-[(l-phenyl ethylamino)-methyl]-
hexanoic acid
(i?,S)-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid (5.0 g) is dissolved in
methanol (20 mL) and (i?5)-l,l'-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 N 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 (5)-l,l'-bi-2-naphthol (1.56 g) having 95%
ee.
The acid aqueous solution which contains hydrochloride salt of (R,S)-3-[(l -phenyl
ethylamino)-methyl]-hexanoic acid is neutralized with dilute solution of sodium bicarbonate to
recover the (i?,5^-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid (0.85 g).
Example 16: Separation of (R)-l,l'-bi-2-naphthol from (RS)-l,l'-bi-2-naphthol via
formation of diastereomeric co-crystal with (R,R )-3-[(l-phenyl ethylamino)-methyl]-
hexanoic acid
(i J ?)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid (5.0 g) is dissolved in
methanol (20 mL) and (i? - l , -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 IN 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 (i?)-l , -bi-2-naphthol ( 1.5 g) having 99 % ee.
The acid aqueous solution which contains hydrochloride salt of (R,R)-3-[(\ -phenyl
ethylamino) -methyl] -hexanoic acid is neutralized with dilute solution of sodium bicarbonate to
recover the (i?,i?)-3-[(l-phenyl ethylamino)-methyl] -hexanoic acid (0.9 g).
Example 17: Separation of (R)-l,l'-bi-2-naphthoI from (RS )-l,l'-bi-2-naphthoI via
formation of diastereomeric co-crystal with (S,R )-3-[(l-phenyl ethylamino)~methyl]-
hexanoic acid.
(5',i?)-3-[(l -phenyl ethylamino)-methyl] -hexanoic acid (5.0 g) is dissolved in
methanol (20 mL) and (i S - l , -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 IN 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 (i?)-l,l'-bi-2-naplitb.ol (1.25 g) having 95 %
ee
The acid aqueous solution which contains hydrochloride salt of (R,R)-3-[{\ -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)-l,l'-bi-2-naphthol via formation of diastereomeric cocrystals
by sequential addition of (S,S )-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid
and (R,R )-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid.
(i 5 - l , l '-bi-2-naphthol (5.75 g) is dissolved in methanol (20 mL) and (¾S>3-[(1 -phenyl
ethylamino)-methyl]-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 IN
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 (5)-l,l'-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 ethylamino)-methyl]-hexanoic acid (0.95 g).
(i?,i?)-3-[(l-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 °C. 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 IN
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 (i?)-l,l'-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)-l,l'-bi-2-naphthol via formation of diastereomeric cocrystals
by sequential addition of (R,S )-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid
and (S,R )-3-[(l-phenyl ethylamino)-methyl]-hexanoic acid.
( ? )- l ,l '-bi-2-naphthol (5.75 g) is dissolved in methanol (20 mL) and (R,S)-3-[(l -phenyl
ethylamino)-methyl]-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 IN
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 obtai
optically pure (,S)-l,l'-bi-2-naphthol (2.0 g) having 98 % ee (yield 70%).
The acid aqueous solution which contains hydrochloride salt of (R,S)-3-[(l -phenyl
ethylamino)-methyl]-hexanoic acid is neutralized with dilute solution of sodium bicarbonate to
recover the (R,S)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid (0.8 g).
(5',i?)-3-[(l -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 IN
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 (i?)-l,l'-bi-2-naphthol (1.7 g) having 98 % ee (yield 65%).
The acid aqueous solution which contains hydrochloride salt of S,R) -3-[ -phenyl
ethylamino)-methyl]-hexanoic acid is neutralized with dilute solution of sodium bicarbonate to
recover the (5",^-3-[(1 -phenyl ethylamino)-methyl]-heXanoic acid (0.8 g).
Example 20: Co-crystal formation of 5-methyl-3-[((R )-l-phenyl-ethylamino)-methyl]-
hexanoic acid with (R )-l,l'-bi-2-naphthol
5-Methyl-3-[((i?)-l-phenyl-ethylamino)-methyl] -hexanoic acid (0.2 g) is dissolved in
methanol (5 mL) and (i?)-l,l'-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 to obtain co-crystal (0.3 g); Fig 14. PXRD of co-crystals of (i?,5)-3-[(l -phenyl
ethylamino)-methyl]-hexanoic acid : (Sj-l,l'-bi-2-naphthol.
Example 21: Co-crystal formation of 5-Methyl-3-[((R )-l-phenyl-ethylamino)-methyl]-
hexanoic acid with (S )-l,l'-bi-2-naphthol
5-Methyl-3-[((R)-l-phenyl-ethylaiTiino)-rnethyl]-hexanoic acid (0.2 g) is
dissolved in methanol (5 mL) and ( -l -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.
CLAIMS
1. A method of separation of the optically pure enantiomers of racemic (RS)-l,V-bi-2-
naphthol of formula (I)
(I)
comprising the steps
(i) reaction of racemic (i?S -l ,l ' -bi-2-naphthol of formula (I) with (5,5)-3-[(lphenylethylamino)-
methyl]-hexanoic acid of the formula (II) or (R,R)-3-[(la
(III)
(P) (HI)
to precipitate the first co-crystal of (,S)-(-)-l , -bi-2-naphthol with S,S - -[ -
phenylethylamino)-methyl]-hexanoic acid or (i?)-(+)-l,l'-bi -2-naphthol with (R,R)~3-[(lphenylethylamino)-
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 Brensted acid to obtain
the (S)-(-)-l,l '-bi-2-naphthoi or (£)-(+)- '-bi-2-naphthol,
(iv) addition of either (i?,i?)-3-[(l-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 (i?)-(+)-l,l'-bi -2-naphthol with (i?,i?)-3-[(lphenylethylamino)-
methyl] -hexanoic acid or ( S)-(-)-l,l'-bi -2-naphthol with (S,S)-3-[(lphenylethylamino)-
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 Br0nsted acid and
recovering the (£)-(+)- l,l'-bi -2-naphthol or (^~(-)-l,l'-bi -2-naphthol.
2 . A method of separation of the optically pure enantiomers of racemic (i? -l ,l ' -bi-2-
naphthol of formula (I)
comprising the steps
(i) reaction of racemic (i?5)-l,l'-bi-2-naphthol of formula (I) with (i ,S)-3-[(lphenylethylamino)-
methyl]-hexanoic acid of the formula (VI) or (S,R)-3-[(\-
phenylethylamino)-methyl]-hexanoic acid of formula (VII)
(VI) (VII)
to precipitate the first co-crystal of (S)-(-)-l,l'-bi-2-naphthol with (R,S)-3-[(lphenylethylamino)-
methyl]-hexanoic acid or (i?)-(+)-l l'-bi-2-naphthol with (¾R)-3-[(lphenylethylamino)-
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 Bmnsted acid to obtain
the ( -)- '-bi-2-naphthol or (£)-(+)- l,l'-bi-2-naphthol
(iv) addition of either (5,i?)-3-[(l-phenylethylamino)-methyl]-hexanoic acid or (R,S)-3-
[(l-phenylethylamino)-methyl]-hexanoic acid to the mother liquor obtained in the step
(ii) to precipitate the second co-crystal of (#)-(+)- l,l'-bi-2-naphthol with ( ', - - . -
phenylethylamino)-methyl]-hexanoic acid or (5)-(-)-l,l'-bi-2-naphthol with (R,S)-3-[(lphenylethylamino)-
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 Bransted acid and
recovering the (i?)-(+)-l,l'-bi-2-naphthol or ( (-)-l,l'-bi-2-naphthol.
3. A method according to claim 1 or 2 wherein the optically pure enantiomers of racemic
(i S)-l,l'-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 (l) 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 (5', )-3-[(1-
phenylethylamino)-methyi]-hexanoic acid or (i?,i?)-3-[(l-phenylethylamino)-methyl]-
hexanoic acid to racemic (i?5)-l,l'-bi-2-naphthol is 0.5 to 1.5, preferably 0.5.
9. A method according to claim 2 wherein the molar ratio of (i , -3-[(l -
phenylethylamino)-methyl]-hexanoic acid or (S',i?)-3-[(l-phenylethylamino)-methyl]-
hexanoic acid to racemic (i?5)-l,l'-bi-2-naphthol is 0.5 to 1.5, preferably 0.5.
10. A method according to claim 1 and 2 wherein the Bmnsted 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 ( ,,5)-3-[(l-phenylethylamino)-methyl]-hexanoic acid : ( -(-)- ,l'-bi-2-
naphthol of the formula (IV)
(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-
[(l-phenylethylamino)-methyl]-hexanoic acid and ( -(-)-l , -bi-2-naphthol is 1:1.
17. A co-crystal (R,R)-3-[(l -phenyl ethylamino)-methyl]-hexanoic acid : (i?)-(+)-l,l'-bi-
2-naphthol of the formula (V)
(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 ( , ) -
3-[(1 -phenylethylamino)-methyl]-hexanoic acid and (i?)-(+)-l,l'-bi-2-naphthol is 1:1.
22. A co-crystal (i?,6)-3-[(l-phenylethylamino)-methyl]-hexanoic acid : (5)-(-)-l,l'-bi-2-
naphthol of the formula (VIII)
(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, 4.69 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 (-) 18.46°.
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 (i?,5)-3-
[(1-phenylethylamino) -methyl]-hexanoic acid and ( -(-)- l,l'-bi-2-naphthol is 1:1.
27. A co-crystal ( ' i?)-3-[(l-phenylethylamino)-methyl]-hexanoic acid : (i?)-(+)-l,l'-bi~
2-naphthol of the formula (IX)
(IX)
characterized by the powder X-ray diffraction peaks at the 2-theta 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 (i?)-(+)-l,l'-bi-2-naphthol is 1:1.
32. A co-crystal of diastereomeric mixture of compound [XVII] and [XVIII] 5-methyl-3-
[((i?)-l-phenyl-ethylamino)-methyl]-hexanoic acid with : (i?)-(+)-l,l'-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