OPTICALLY PURE 1. 1'-BI-2-NAPHTHOL

Field of Invention:

The invention relates to formation of novel three component co-crystal between diastereomeric mixture of 3-aIkyl-4-((S)-1'-phenylethylamino)butanoic acid and optically pure 1 ,1'-bi-2-naphthol, and novel, improved and efficient method for resolution of racemic 1 ,1 '-bi-2-naphthol to obtain optically pure (S -(-)-1 ,1'-bi-2- naphthol and/or (R)-(+)-1 , 1 '-bi-2-naphthol in 99 % ee and high yield, through formation of three component co-crystal.

Background of the Invention:

Co-crystals are crystals that contain two or more different molecular components, which are solid at ambient temperature and pressure. Whenever, one of the solid components in the co-crystal is a liquid such as solvents, alcohol or water, then it is called a solvate or hydrate. In case of salts, wherein, all the molecular components i.e. solid or liquid are held together through ionic interactions i.e. ionic bonds, in co- crystals the different molecular entities are held together in the crystal lattice by non covalent bonds.

As mentioned co-crystals are formed because of hydrogen bond interactions between the molecular components, however, other non covalent interactions such as TT- π stacking, van der Waals forces and dipole -dipole interactions also play significant role for the formation of co-crystals (J. Pharm Sci 2006, 95, 499-516; Crystal Engg. Commun, 2003, 5, 466-67; J. Chem. Soc: Chem. Comm. 1990, 589- 591).

It could be seen from above that, co-crystal is the result of molecular recognition between different molecular species in the crystal. In short, co-crystals are homogenous, single crystalline unit cells with well defined stoichiometry such as AB, AB ₂ , etc., where both A & B are distinct solid components.

A variety of co-crystals can exist such as

i) Equivalent stoichiometry between different molecules i.e. neutral components (AB)

ii) Varying stoichiometry between different molecules (AB ₂ )

iii) Neutral component along with ionic component such as hydrochloride (AB.HCI)

iv) Polymorphs

v) Neutral components along with solvent i.e. solvate of co-crystal (AB.H ₂ O).

Co-crystal formation is a spontaneous chemical reaction between the different solid molecules in a solvent, hence the resulting co-crystal has different free energy than the individual molecules.

Co-crystals generate different crystalline form and significantly modify the physical properties of the individual components such as i) solubility, ii) dissolution rate, iii) chemical stability, iv) mechanical behavior, v) moisture uptake, etc.

The statistical data published by Vishweshwar et.al. based on Cambridge Structural Database (CDS) of single crystal structure of polymorphic single components and co-crystal reports only 1.1 % co-crystals out of total number of organic single crystal structures reported (J. Pharm Sci 2006, 95, 499-516).

As per the above report, it could be concluded that incidence of occurrence of co- crystal as such is very low and also it is to be emphasized that most of the reported co-crystals either have equivalent stoichiometry (AB) or varying stoichiometry (AB ₂ ). There are few examples of three component co-crystals, however, in most of them third component is liquid and the present inventors were able to retrieve only one example where all the three components of the co-crystal i.e. 2,2-dihydroxybiphenyl, phenazine and acridine (Structural Chemistry, 10 (6), 1999, 429-431) are solids.

In "Dutch resolution", three or more components of which many times all are solids are used. But it is to be noted that this resolution is essentially through diastereomeric salt formation and not through co-crystal formation as defined above (Angew.Chem.lnt.Ed. 1998, 37(17), 2349-2354; Synthesis, 2003, 1626-1638). For instance, the resolution of racemic 4-bromo-(a)-methyl benzyl amine through "Dutch resolution" technique is reported using mixture of optically pure resolving agents i.e. mandelic acid, p-methylmandelic acid, and p-bromomandelic acid in 1 :1 :1 ratio, wherein a mixture of three diastereomeric amine mandelate, p-methyl mandelate and p-bromomandelate are formed.

As per knowledge of present applicant, there is no report of a co-crystal containing three solid components ABC, wherein, B & C are diastereomers.

It is very difficult to predict which two molecules could form co-crystal, although certain guidelines are provided in the literature on the basis of common hydrogen bonded synthons (Angew. Chem. Int.Ed. 2007, 46, 8342-8356; J. Pharm Sci 2006, 95, 499-516), some of which are represented below.

Presence of above synthons is necessary but not sufficient for formation of two or three component co-crystal. Furthermore, the role of solvent in co-crystal formation is not fully understood and an appropriate solvent in which co-crystal formation can be performed with maximum efficiency requires innovation.

As mentioned earlier only presence of synthons is not sufficient for formation of co- crystal and it could also be concluded from work of the present applicant in which homologous series of 3-alkyl-4-((S)-1 '-phenylethylamino)butanoic acid [A], all solids, having same "Cisoid cyclohexane" conformation, are used for the co-crystal formation and results are summarized in table 1.

|A] Table 1 : Co-crystal formation with Homologous Series of 3-alky l-4-((S)-1 '- phenylethylamino)butanoic acid [A]

In PCT application No. PCT/IN2010/000141 , the present applicant demonstrated the process for resolution of (RS) - 1 ,1'-bi-2-naphthol [IX] through co-crystal formation with optically pure 3-alkyl-4-((S)-1 '- henylethylamino)butanoic acid.

(IX) As per the disclosure in the pending PCT application PCT/IN2010/000141 of the present applicant, only compounds [VI], Ml] and Mil] yielded the co-crystal with optically pure 1 ,1 '-bi-2-naphthol. It is to be noted that co-crystal obtained from compound M] and Ml] are binary co- crystals, which give the better enantiomeric excess and yield for resolution of (RS) - 1 ,1'-bi-2-naphthol [IX] as compared to compound Mil], which yielded supposedly ternary co-crystal with optically pure (R) 1 ,1 '-bi-2-naphthol. However, the resolution of (RS)-1 , 1 '-bi-2-naphthol [IX] to obtain optically pure (S) - 1 ,1 '-bi-2-naphthol through binary co-crystal formation with compound M] is more efficient and give high enantiomeric excess as compared to the resolution of (RS)- 1 ,1'-bi-2-naphthol [IX] to obtain optically pure (S) - 1 ,1'-bi-2-naphthol through co- crystal formation with compound Ml] and to obtain optically pure (R) - 1 ,1 '-bi-2- naphthol through co-crystal formation with compound Mil].

As expected and found to be true, the antipodes of compound M] and Ml] forms the co-crystal with antipode of (S)-1 ,1 '-bi-2-naphthol i.e. (f?)-1'-bi-2-naphthol. Similarly, it is also observed that the resolution of (RS)-1 ,1 '-bi-2-naphthol [IX] to obtain optically pure (R) - 1 ,1 '-bi-2-naphthol through formation of binary co-crystal formation with 3(R)-propyl-4-((R)-1 '-phenylethylamino)butanoic acid is more efficient and give high enantiomeric excess as compared to the resolution of (RS)-1 ,1'-bi-2- naphthol [IX] to obtain optically pure (R) - 1 ,1 '-bi-2-naphthol through formation of binary co-crystal with 3(S)-propyl-4-((R)-1 '-phenylethylamino)butanoic acid.

In earlier patent application PCT/IN2010/000141 , the present applicant had described the detailed method for synthesis of compound M] and Ml] and reaction scheme is depicted in scheme I. Scheme I:

As mentioned, binary co-crystal obtained from compound [VI] gives the desired enantiomeric purity, however method for obtaining compound [VI], as described in the PCT application PCT/IN2010/000141 is tedious and cumbersome, and moreover as compound [VII] is not desirable for resolution, because enantiomeric excess obtained is lower as compared to enantiomeric excess obtained from that of compound [VI], hence, compound [VII] would add to the effluent and would render the process of resolution of (RS)-1 ,1'-bi-2-naphthol economically less attractive.

Hence it would have been ideal if mixture of compound [VI] and [VII], i.e. diastereomeric mixture is used for the resolution to obtain desired enantiomeric purity, thereby increasing the process efficiency and decreasing the overall cost. Moreover it would eliminate the separation of diastereomers i.e. compound [VI] and [VII]. The present invention provides a solution to all such problems.

The merits of present invention are:

1) Formation of three component co-crystal through mixture of diastereomers and optically pure 1 ,1'-bi-2-naphthol

2) Resolution of racemic 1 , 1 '-bi-2-naphthol to obtain optically pure 1 ,

1'-bi-2-naphthol through three component co-crystal formation in high enantiomeric excess (99 % ee) and overall yield (77%) 3) Enhancement of the process efficiency which results in decrease in the overall cost.

4) Safe, easy to operate and scalable process.

5) Reusability of 3-propyl-4-((S)-1'-phenylethylamino)butanoic acid for resolution of racemic 1 , 1 '-bi-2-naphthol through three component co-crystal formation.

Objects of the Invention:

Thus it is an object of the present invention to prepare a three component co-crystal containing mixture of diastereomers and optically pure 1 ,1'-bi-2-naphthol.

Further object of the present invention is to design a process for resolution of racemic 1 , 1 '-bi-2-naphthol to obtain optically pure 1 ,1'-bi-2-naphthol through three component co-crystal formation in high enantiomeric excess (99 % ee) and overall yield (77%).

Another object of the present invention is to enhance the process efficiency which result into decrease in the overall cost of resolution of 1,1'-bi-2-naphthol. Yet another object of the present invention is to provide a safe, easy to operate and scalable process for resolution of 1 ,1'-bi-2-naphthol.

It is also an object of the present invention to establish reusability of 3-propyl-4-((S)- 1'-phenylethylamino)butanoic acid for resolution of racemic 1 , 1'-bi-2-naphthol through three component co-crystal formation.

Summary of Invention:

The invention provides a ternary co-crystal consisting of 1:0.5:0.5 molar proportion of (S)-1 ,1'-bi-2-naphthol, 3(S)-propyl-4-[(S)1'-phenyl-ethylamino]-butanoic acid and 3(R)-propyl-4-[(S)1'-phenyl-ethylamino]-butanoic acid having characteristic powder X-ray diffraction pattern and differential scanning calorimetric peaks. Other aspect of the invention is preparation of a ternary co-crystal consisting of 1 :0.5:0.5 molar proportion of (S)-1 ,1'-bi-2-naphthol, 3(S)-propyl-4-[(S)1 '-phenyl- ethylaminoj-butanoic acid and 3(R)-propyl-4-[(S)1 '-phenyl-ethylamino]-butanoic acid involving steps of

(a) adding (S)-1 ,1-bi-2-naphthol to the solution of 3-propyl-4-((S)-1 '- phenylethylamino)butanoic acid in methanol;

(b) stirring the mixture formed in (a) at 50°C for one hour;

(c) cooling the reaction mixture to 25 to 35°C and filtration of the crystalline product; and

(d) drying the product till constant weight.

Another aspect of the present invention is preparation of a ternary co-crystal consisting of 1 :0.5:0.5 molar proportion of (S)-1 ,1'-bi-2-naphthol, 3(S)-propyl-4- [(S)1'-phenyl-ethylamino]-butanoic acid and 3(R)-propyl-4-[(S)1 '-phenyl-ethylamino]- butanoic acid involving steps of,

(a) adding (f?S)-1 ,1-bi-2-naphthol to the solution of 3-propyl-4-((S)-1 '- phenylethylamino)butanoic acid in methanol;

(b) stirring the mixture formed in (a) at 50°C for two hours;

(c) cooling the reaction mixture to 25 to 35°C and filtration of the crystalline product; and

(d) drying the product till constant weight.

Further aspect of the present invention is resolution of (S)-1 ,1'-bi-2-naphthol from (RS)-1 ,1'-bi-2-naphthol comprising preparation of ternary co-crystal consisting of 1 :0.5:0.5 molar proportion of (S)-1 ,1'-bi-2-naphthol, 3(S)-propyl-4-[(S)1'-phenyl- ethylamino]-butanoic acid and 3(R)-propyl-4-[(S)1 '-phenyl-ethylamino]-butanoic acid as an intermediary step.

Yet another aspect of the present invention is resolution of (S)-1 ,1'-bi-2-naphthol from (RS)-1 ,1'-bi-2-naphthol comprising following steps: a. Addition of (RS)-1 ,1-bi-2-naphthol to the solution of 3-propyl-4-((S)-1 '- phenylethylamino)butanoic acid in methanol.

b. Agitation of the mixture formed in (a) at 50°C for two hours.

c. Cooling of the reaction mixture to 25 to 35°C and filtration of the crystalline product.

d. Suspension of the product obtained in step c in biphasic mixture of ethyl acetate and dilute hydrochloric acid and stirring the mixture for 30 to 45 minutes.

e. Isolation of the product from organic phase.

f. Recovery of 3-propyl-4-((S)-1 '-phenylethylamino)butanoic acid from aqueous phase obtained after step d.

Detailed Description of the Invention:

The invention embodies a three component co-crystal containing diastereomeric mixtures of 3-alkyl-4-((S)-1'-phenylethylamino)butanoic acid and optically pure 1 , 1'- bi-2-naphthol and method for obtaining such three component co-crystals.

According to one embodiment of the invention in three component co-crystals, two components are diastereomers.

The invention also embodies method for obtaining optically pure enantiomers of 1 , 1'-bi-2-naphthol, having optical purity of > 99% with high yield.

According to one embodiment of the invention, chiral separation of 1 , 1 '-bi-2- naphthol to optically pure (S)-enantiomer of 1 , 1 '-bi-2-naphthol is obtained via formation of three component co-crystal with diastereomeric mixture of 3-propyl-4- ((S)-1 '-phenylethylamino)butanoic acid.

The method of manufacturing essentially consists of addition of desired antipodes of diastereomeric mixture of 3-propyl-4-(1'-phenylethylamino)butanoic acid to a solution of (RS)-1 ,1'-bi-2-naphthol [IX] in methanol, wherein the corresponding antipode of 1 ,1 '-bi-2-naphthol forms three component co-crystal.

The co-crystal thus formed crystallizes out leaving the other antipodes 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, decantation etc.

Other antipode of diastereomeric mixture of 3-propyl-4-(1'(S)- phenylethylamino)butanoic acid is added to mother liquor, where the other antipode of (S)-1 , 1 '-bi-2-naphthol forms the three component co-crystal.

The co-crystal, thus obtained is then isolated from the mother liquor by using techniques known in the art like filtration, centrifugation, decantation etc. The co-crystal is then decomposed with a hydrogen ion source like a Bronsted acid such as dilute hydrochloric acid, dilute sulfuric acid, acetic acid etc. to obtain optically pure 1 ,1'-bi-2-naphthol.

Diastereomeric mixture of 3-propyl-4-(1'-phenylethylamino)butanoic acid is recovered from acidic aqueous solution after neutralization with sodium bicarbonate and recycling in the process, thereby making the whole process very cost effective and easily operable.

Thus, when (RSJ-1 ,1'-bi-2-naphthol [IX] is reacted with diastereomeric mixture of 3- propyl-4-((S)-1'-phenylethylamino)butanoic acid [XIII] (i.e. a 1 :1 mixture of compounds [VI] and [VII]),

XIII (3RS, l'S)

there is formation of the easily separable co-crystal with (SM-)-1 ,1'-bi-2-naphthol, which is separated by filtration, leaving behind (R (+)-1 ,1'-bi-2-naphthol in mother liquor.

The co-crystal [XIV] i.e. co-crystal obtained from diastereomeric mixture of 3-propyl- 4-((S)-1'-phenylethylamino)butanoic acid i.e compound [XIII] and (S (-)-1 ,1'-bi-2- naphthol is further purified from methanol.

(xiv)

Thus obtained co-crystal is three component co-crystal consisting of (S)-3-propyl-4- ((S)-1'-phenylethylamino)butanoic acid, (R)-3-propyl-4-((S)-1 '- phenylethylamino)butanoic acid and (S -(-)-1.1'-bi-2-naphthol in 0.5:0.5:1 molar ratio. The co-crystals [XIV] are decomposed in biphasic mixture of ethyl acetate and dilute (1N) hydrochloric acid (1 :1) at room temperature. Optically pure (S)-1 ,1 '-bi-2-naphthol is obtained from ethyl acetate layer having 99 % ee, based on chiral HPLC analysis.

Aqueous solution contain the hydrochloride salt of 3-propyl-4-((S)-1 '- phenylethylamino)butanoic acid, which is further neutralized with aqueous solution of sodium bicarbonate to obtain the 3-propyl-4-((S)-1 '-phenylethylamino)butanoic acid and its HPLC ananlysis shows that disetereomers are in 1 :1 ratio.

Hence from above results and through material balance, it is concluded that molar ratio of (S)-1 ,1 '-bi-2-naphthol : (S)-3-propyl-4-((S)-1 '-phenylethylamino)butanoic acid : (R)- 3-propyl-4-((S)-1 '-phenylethylamino)butanoic acid is 1 :0.5:0.5.

Compound [XIII] (racemate containing 1 :1 mixture of pure isomers [VI] and [VII]) was prepared from 5-hydroxy-4-/7-propyl-5/-/-furan-2-one [X] as per the chemistry described in scheme 1 herein above.

5-hydroxy-4-A7-propyl-5 - -furan-2-one [X] when reacted with (S)-(a)-methyl benzyl amine [XI] gives the compound [XII]. Hydrogenation of compound [XII] in methanol gives the diastereomeric mixture [XIII], (Scheme II)

5-hydroxy-4-n-propyl-5 - -furan-2-one [X] when reacted with (R)-(a)-methyl benzyl amine [ΧΓ] gives compound [XI Γ]. Hydrogenation of compound [ΧΙΓ] gives the diastereomeic mixture of antipodes of [XIII], i.e. compound [XIII ^* ] (Scheme II).

Scheme II: Synthesis of Compound XIII and its antipode

In all cases, the co-crystal formation of diastereomeric mixture of 3-propyl-4-((S)-1 '- phenylethylamino)butanoic acid with (S)-(-)-1 ,1'-bi-2-naphthol is carried out in an alcoholic solvent, preferably methanol.

In all cases, the co-crystal formation of (S -(-)-1 ,1'-bi-2-naphthol with diastereomeric mixture of 3-propyl-4-((S)-1 '-phenylethylamino)butanoic acid is carried out at a temperature range of 25-60° C, preferably at 50° C.

Molar ratio of diastereomeric mixture of 3-propyl-4-((S)-1 '-phenylethylamino)butanoic acid to compound [IX] or (S^-(-)-1 ,1'-bi-2-naphthol varies from 0.5 to 1.5 mol equivalents; preferably 0.6 mol equivalent is used. The co-crystals of (S -(-)-1 ,1'-bi-2-naphthol with diastereomeric mixture of 3-propyl- 4-((S)-1 '-phenylethylamino)butanoic acid are decomposed in a biphasic mixture of ethyl acetate: dilute hydrochloric acid (1 :1) at room temperature. The co-crystals of (S (-)-1 ,1'-bi-2-naphthol with diastereomeric mixture of 3-propyl- 4-((S)-1'-phenylethylamino)butanoic acid are characterized (see table 2) by the powder X-ray diffraction peaks at the 2-theta values 8.41 , 9.38, 10.32, 12.16, 15.52, 15.51 , 17.84, 17.95, 19.16, 20.37, 21.74, 22.55, 24.44, 25.65, 28.40, 29.15, 29.69, 31.31 , 33.54, 34.40 and 35.43

Lattice parameters for ternary co-crystal are calculated from observed powder X-ray diffraction pattern using DICVOL04 software and found to be α, β, γ = 90 ° and a = 10.1831 A, b= 11.3657 A, c=26.2492 A and having orthorhombic crystal system.

Diffraction pattern obtained from above calculated lattice parameters are superimposable with observed diffraction pattern. In earlier patent application PCT/IN2010/000141 , the present applicant had carried out the single crystal X-ray diffraction analysis of binary crystal obtained from compound [VI] and [VII], which shows that in both cases co-crystal is orthorhombic, with space group P212121 and having practically equal a,b,c values. Moreover, powder X-ray diffraction pattern for both the co-crystal is similar.

Co-crystal obtained from compound [XIII] and (S -(-)-1 ,1'-bi-2-naphthol i.e. ternary co-crystal shows the similar powder x-ray diffraction pattern to that of binary co- crystal system, as reported in the earlier patent application of the present applicant. Solubility of co-crystal [XIV] (i.e. a co-crystal of compound [XIII] with (S -(-)-1 ,1'-bi-2- naphthol) has been found to be 3gm/100ml at 30°C in methanol and is compared with the solubility of both the binary co-crystal systems, which is given in figure 2. Temperature dependence of solubility i.e. dS/dT is calculated and have been found to be 0.1308, 0.1056 and 0.1045 mol/L°C respectively. Difference in the solubility and dS/dT is presumably due to difference in the physical characteristic i.e. lattices energy binding in all three co-crystal systems. The co-crystal of (S (-)-1 ,1'-bi-2-naphthol with diastereomeric mixture of 3-propyl-4- ((S)-1'-phenylethylamino)butanoic acid is characterized by differential scanning calorimetry peak at about 189.23 ° C.

The co-crystals of (SM-)-1 ,1'-bi-2-naphthol with diastereomeric mixture of 3-propyl- 4-((S)-1 '-phenylethylamino)butanoic acid have specific optical rotation of (-) 17.73 ° (c=1% in methanol) Moreover differential scanning calorimetry shows clear difference in the all three co- crystal systems i.e. two binary co-crystal and ternary co-crystal have different endotherms as depicted in the figure 3.

Difference in the free energy of dissolution is calculated according to following formula

AG(A-B) = T In (SA/SB)

Where, AG ₍ A-B ₎ is difference in free energy of dissolution of two co-crystal A and B, SA is solubility of co-crystal A in mol/L, and SB is solubility of co-crystal B in mol/L.

It is observed that difference in free energy of dissolution in the binary co-crystal between compound [VI] and (S)-1 ,1'-bi-2-naphthol and binary co-crystal between compound [VII] & (S)-1 ,1'-bi-2-naphthol is 0.18 kcal/mol. Whereas, difference in free energy of dissolution between binary co-crystal between compound [VI] and (S)-1 ,1'-bi-2-naphthol and ternary co-crystal between compound [XIII] &(S)-1 ,1'-bi-2-naphthol is 0.058 kcal/mol and which is as expected in the view of melting point difference between above two co-crystals i.e. 4.23 °C. Also, difference in free energy of dissolution in binary co-crystal between compound [VII] and (S)-1 ,1'-bi-2-naphthol and ternary co-crystal between compound [XIII] &(S)- 1 , 1 '-bi-2-naphthol is 0.24 kcal/mol which is as expected in the view of melting point difference between above two co-crystals i.e. 12.23 °C

The co-crystals of (SH-)-1 ,1 '-bi-2-naphthol with diastereomeric mixture of 3-propyl- 4-((S)-1 '-phenylethylamino) butanoic acid have solubility of 3gm /100ml in methanol at 30 °C and solubility curve at different temperature is depicted in figure 2.

Powder X-ray diffraction pattern and FTIR spectra of various binary and ternary co- crystal systems is summarized in table 2 below.

Table 2 Physical properties of co-crystals of [VI], [VII], and [XIII] with (S)-(-)- 1 ,1 '-bi-2-naphthol and co-crystal of compound [VIII] with (Rj-(-)-1 ,1'-bi-2- naphthol.

Solid state ¹³ CNMR spectra of the ternary co-crystal of (S -(-)-1 ,1'-bi-2-naphthol with diastereomeric mixture of 3-propyl-4-((S)-1 '-phenylethylamino)butanoic acid shows characteristic pattern (Figure 4). Comparison of solid state ¹³ CNMR of a ternary co- crystal of (SM-)-1 ,1'-bi-2-naphthol an diastereomeric mixture of 3-propyl-4-((S)-1 '- phenylethylamino)butanoic acid with that of binary co-crystal of (SM-)-1 ,1'-bi-2- naphthol and 3(S)-propyl-4-((S)-1'-phenylethylamino)butanoic acid (figure 5) reveals characteristic peaks between δ 60 - 110 in solid state ¹³ CNMR spectra of the ternary co-crystal (see figure 4 and Table 3).

Table 3: Solid state ¹³ CNMR δ ppm values for Co-crystal of compound [XIII] with (S -1 ,1'-bi-2-naphthol and Co-crystal of compound [VI] with (Sj-1 ,1'-bi-2-naphthol

Ternary Binary

Co- Co- crystal,* crystal *

(δ ppm) (δ ppm)

105.2771 -

103.2496 -

95.056 -

86.055 -

82.8564 -

78.8824 -

77.7888 -

76.7734 -

74.4194 -

72.3204 -

71.0622 -

68.8477 -

67.5598 -

66.0089 -

64.8005 -

63.7978 -

- 57.9107

58.0199 -

56.3422 -

52.9887 52.847

- 48.6523

49.8173 - *Ternary Co-crystal: co-crystal of compound [XIII] with (S)-1, 1'-bi-2-naphthol

Binary Co-crystal: co-crystal of compound [VI] with (S)-1, 1'-bi-2-naphthol

Nomenclature used for the compounds mentioned herein are as understood from the CambridgeSoft® ChemOffice software ChemDraw Ultra version 6.0.1. The enantiomeric excess (ee) was determined by HPLC using a Shimadzu LC 2010 system equipped with a chiral column (Chiral Pak IA, 4.6mm x 250mm, 5μπι), column oven temperature 40 °C and UV visible detector (230 nm); mobile phase used was n-hexane (94) :n-butanol (5) : ethanol (1 ): trifluoroacetic acid (0.3 ml_) with flow rate 1 mUmin, injection volume 20 μΙ. The diastereomeric excess (de) is determined by HPLC using a Shimadzu LC 2010 system equipped with a Inertsil Sil column (4.6mm x 250mm, 5μηη), column oven temperature 25 °C and UV visible detector (210 nm); mobile phase used was n-hexane (94): ethanol (05): trifluoroacetic acid (0.2) : triethylamine (0.1 ) with flow rate 1 mL/min, injection volume 20 μΙ. Powder X-ray diffraction was recorded on PANalytical B. V. Netherlands model PN3040/60X'Part Pro and Lattice parameters were calculated by using Dicvol04 software. NMR spectra were obtained at 200 and 400 MHz Bruker instruments, with CDCb as solvent; chemical shifts (δ) are given in ppm relative to tetramethylsilane (6 = 0 ppm). Solid state NMR spectra are acquired using BRUKER AVANCE 400 DSX spectrometer operating at 400MHz for the ¹ H, 100 MHz for ¹³ C and equipped with a BRUKER 4mm solid-state CP MAS probe. The spinning rate was set to 8 kHz. IR spectra were recorded on Perkin Elmer Spectrum (Model: Spectrum 100) and absorption bands are given in cm ^"1 . DSC was recorded on Perkin Elmer model Diamond DSC at the rate of 10 °C/min, and endothermic peak was recorded in °C. Solubility measurements were performed on HEL Auto-lab instrument with turbidity probe.

Description of the Figures:

Figure 1 : PXRD of co-crystal [XIV] Figure 2: Solubility of co-crystals of [VI], [VII] and [XIII] with (Sj-1 ,1 '-bi-2-naphthol Figure 3: Differential scanning calorimetry of co-crystals of [VI], [VII] and [XIII] with (Sj-1 ,1 '-bi-2-naphthol

Figure 4: Solid state ¹³ CNMR spectra of ternary co-crystal of compound [XIII] with (S -1 ,1 '-bi-2-naphthol.

Figure 5: Solid state ¹³ CNMR spectra of binary co-crystal of compound [VI] with (S)- 1 ,1 '-bi-2-naphthol.

The present invention is illustrated in more detail by referring to the following Examples, which are not to be construed as limiting the scope of the invention.

Example 1 : Synthesis of 5-hydroxy-4-n-propyl-5H-furan-2-one (Reference: J. Org. Chem 1981 , 46, 4889^894)

Heptane (394 ml_) and morpholine (127.5 ml_) were added into the reactor while stirring. The mixture was cooled to 0°C and glyoxylic acid (195 g, 150 ml_, 50 wt% in water) was added and after complete addition reaction mixture was heated to 20°C and stirred for 1 h. To the above reaction mixture n-valeraldehyde (148.8 ml_) was added slowly and after complete addition reaction mixture was heated to 45°C and stirred for 20 h. After which reaction mixture was cooled to 20°C and 37% aqueous solution of hydrochloric acid (196.9 ml_) was slowly added to the mixture, and further stirred for 2 hours.

After removal of the heptane phase, the aqueous phase was washed three times with heptane. Aqueous phase is extracted with di-/so-propyl ether (3x250 ml_). The combined di /so-propyl ether layers was washed with brine and solvent was evaporated under reduced pressure to obtain 100.0 g of 5-hydroxy-4-n-propyl-5/-/-furan-2-one as light brown oil.

FTIR (neat): 3367, 1735 cm ¹ .

1H NMR (CDCI ₃ , 200 MHz): δ 0.93-1.00 (t, 3H), 1.56-1.67 (q, 2H), 2.31-2.43 (q, 2H), 5.81 (s, 1 H), 6.02 (s, 1 H).

MS (El): C ₇ H ₁₀ O ₃ : 142.06; [M+H] ⁺ : 142.93.

Example 2: Synthesis of 5-hydroxy-4-n-methyl-5H-furan-2-one (Reference: J. Org. Chem 1981 , 46, 4889^894)

Heptane (350 mL) and morpholine (163 g) were added into the reactor while stirring. The mixture was cooled to 0°C and glyoxylic acid (195 g, 150 mL, 50 wt% in water) was added. After complete addition reaction mixture was heated to 20°C and stirred for 1 h. Propionaldehyde (100 g) was added slowly to above reaction mixture and then reaction mixture was heated to 45°C and stirred further for 20 h. After which reaction mixture was cooled to 20°C and 37% aqueous solution of hydrochloric acid (196.9 mL) was slowly added to the mixture and resulting mixture was further stirred for 2 hours.

After removal of the heptane phase, the aqueous phase was washed three times with heptane. The aqueous phase was extracted with di-/ ^' so-propyl ether (3x 250 mL). The combined di-/ ^' so-propyl ether was washed with brine and solvent was evaporated under reduced pressure to yield 43.0 g of 5-hydroxy-4-n-methyl-5/-/-furan-2-one as light brown oil. FTIR (neat): 3367, 1735 cm ^"1 .

¹ H NMR (CDCfe, 200 MHz): δ 1.71 (s, 3H), 5.81 (s, 1 H), 6.02 (s, 1 H).

MS (El): C ₅ H ₆ 0 ₃ : 114.06; [M+H] ⁺ : 114.93. Example 3: Synthesis of 5-hydroxy-4-ethyl-5H-furan-2-one (Reference: J. Org. Chem 1981 , 46, 4889-4894)

Heptane (250 mL) and morpholine (93 g) were added into the reactor while stirring. The mixture was cooled to 0°C and glyoxylic acid (153 g, 50 wt% in water) was added. After complete addition reaction mixture was heated to 20°C and stirred for 1 h. n- butyraldehyde (70 g) was added slowly to above reaction mixture and then reaction mixture was heated to 45°C and stirred further for 20 h. After which reaction mixture was cooled to 20°C and 37% aqueous solution of hydrochloric acid (196.9 mL) was slowly added and resulting mixture was further stirred for 2 h.

After separation of the heptane phase, the aqueous phase was washed three times with heptane. The aqueous phase was further extracted with di-/so-propyl ether (3x 100 mL). The combined di- so-propyl ether layer was washed with brine and solvent was evaporated under reduced pressure to obtain 66.0 g of 5-hydroxy-4-ethyl-5H-furan-2- one, as light brown oil.

FTIR (neat): 3367, 1735 cm ^"1 .

¹ H NMR (CDC , 200 MHz): δ 0.93-1.00 (t, 3H), 2.31-2.43 (q, 2H), 5.81 (s, 1 H), 6.02 (s, 1 H).

MS (El): C ₆ H ₈ O ₃ : 128.13; [M+H] ⁺ : 128.93. Example 4: Synthesis of 5-hydroxy-4-/so-butyl -5H-furan-2-one (J. Org. Chem. 1981 , 46, 4889-4894)

n-Heptane (75.0 mL) and morpholine (17.8 g) were added into the reactor while stirring. The mixture was cooled to 0° C and glyoxylic acid (29.6 g, 50 wt% in water) was added. The mixture was heated to 20° C for 1 hour and then 4-methyl valeraldehyde (20.0 g) was added and then reaction mixture was heated at 45° C for 20 hours. After cooling down to 20° C, a 37 % aqueous solution of hydrochloric acid (30 mL) was slowly added to the mixture, which was then stirred for 2 hours.

After removal of the n-heptane phase, the aqueous phase was washed three times with n-heptane. Di-/so-propyl ether was added to the aqueous phase. The organic phase was removed and the aqueous phase further extracted with di-/so-propyl ether (2x). Combined di-iso-propyl ether layer was washed with brine and solvent was evaporated under reduced pressure. After evaporation of the solvent, 13.0 g of 5-hydroxy-4- /sobutyl-5 - -furan-2-one were obtained as light yellow oil.

FTIR (neat): 3371 , 1738 cm ¹ .

1H NMR (CDCI ₃ , 200 MHz): δ 0.87-0.99 (t, 6H), 1.87-2.01 (m, 1 H), 2.28-2.32 (d, 2H), 5.82 (s, 1 H), 6.11 (s, 1 H).

MS (El): C ₈ Hi ₂ O ₃ : 156.06; [M-H] ^" : 155.09.

Example 5: Synthesis of S-hydroxy-l-JiS^-phenyl-ethy^-n-propyl-I .S-dihydro-pyrrol^- one (S)-a-methyl benzyl amine (8.5 g) was added slowly into solution of 5-hydroxy-4-n- propyl-5H-furan-2-one (10.0 g) in / ^' so-propanol (100 mL) and resulting mixture was stirred for 1 h at room temperature. After completion of the reaction (monitored by TLC, 1 :1 ethyl acetate:hexane), the solvent was evaporated under reduced pressure 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 .

¹ H NMR (CDCI ₃ , 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, 1 H), 5.15 (s, 1 H), 5.70 (s, 1 H), 7.25-7.34 (m, 5H).

MS (El): Ci ₅ H ₁₉ N0 ₂ : 245.14; [M+H] ⁺ : 246.51.

Example 6: Hydrogenation of 5-hydroxy-1-[(S -phenyl-ethyl]-4-propyl-1 ,5-dihydro-

A solution of 5-hydroxy-1-[(S)-phenyl-ethyl]-4-propyl-1 ,5-dihydro-pyrrol-2-one (16.5 g) in /so-propanol (100 mL) was charged in a Parr autoclave reactor followed by addition of 50 % wet palladium-on-carbon (Pd/C) (1.6 g). Reactor was purged with hydrogen gas twice and 3 kg hydrogen pressure was maintained. The progress of reaction was monitored by TLC [Chloroform: methanol (9:1)]. After complete consumption of starting material, the reaction was stopped. In the reaction, diastereomers were separated, (S)-3-propyl-4-((S)-1'-phenylethylamino)butanoic acid precipitated out from the reaction media and (R)-3-propyl-4-((S)-1 '- phenylethylamino)butanoic acid remained dissolved in the reaction media. After completion of reaction, the reaction mixture was filtered and filtrate was concentrated under vacuum to obtain a semi solid material, which was suspended in cyclohexane (300 ml_) and stirred overnight to yield 6.5 g of (f?)-3-propyl-4-((S)-1 '- phenylethylamino)butanoic acid as a off-white solid obtained after vacuum filtration.

Filtered cake contains Pd/C and (S)-3-propyl-4-((S)-1'-phenylethylamino)butanoic acid which was suspended in methanol and stirred for 20 min to dissolve (S)-3- propyl-4-((S)-1'-phenylethylamino)butanoic acid. Pd/C was separated by filtration. Filtrate was concentrated under vacuum to obtain 6.7 g of (S)-3-propyl-4-((S)-1'- phenylethylamino)butanoic acid as a white solid.

(S)-3-propyl-4-((S)-1 '-phenylethylamino)butanoic acid:

FTIR (KBr pellets): 2960, 1623, 1547 cm ¹ ;

1H NMR (CDCI ₃ , 200 MHz): 6 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, 1 H), 4.12-4.17 (q, 1 H), 7.35-7.42 (m, 3H), 7.47-7.51 (m, 2H); ¹³ C NMR (CDCI ₃ , 50 MHz): 14.0, 19.8, 21.2, 32.7, 36.5, 44.2, 51.1 , 57.4, 127.4, 128.6, 129.2, 138.2, 179.3;

MS (El): C ₁₅ H ₂₃ N0 ₂ : 249.17; [M+H] ⁺ : 250.20

DSC (10 °C/min): Peak at 147.16°C

(ff)-3-propyl-4-((S)-1 '-phenylethylamino)butanoic acid:

FTIR (KBr pellets): 2956, 1619, 1549, 1400 cm ¹ ;

¹ H NMR (CDCI ₃ , 200 MHz): δ 0.76-0.79 (t, 3H), 1.14-1.23 (m,4H), 1.66-1.68 (d, 3H), 2.26-2.30 (m, 2H), 2.53-2.59 (t, 2H), 2.77-2.80 (d, 1 H), 4.06-4.11 (q, 1 H), 7.31-7.57 (m, 5H); ¹³ C NMR (CDCI ₃ , 50 MHz): 14.0, 19.7, 20.5, 33.2, 36.2, 43.7, 51.6, 58.5, 127.5, 128.6, 129.2, 137.8, 179.5;

MS (El): C ₁₅ H2 ₃ N0 ₂ : 249.17; [M+H] ⁺ : 250.05.

DSC (10 °C/min): Peak at 120.1 °C Example 7: Synthesis of 5-hydroxy-1-[(R phenyl-ethyl]-4-isobutyl-1 ,5-dihydro-pyrrol-2- one

(R)-ar-methyl benzyl amine (7.7 g) was added slowly into a solution of 5-Hydroxy-4-/so- butyl-5H-furan-2-one (10.0 g) in /so-propanol (100 mL) and stirred for 1 h at room temperature. After completion of the reaction (monitored by TLC, 1 :1 ethyl acetate:hexane), the solvent was evaporated under reduced pressure in a rotary evaporator to afford 5-hydroxy-1-[(R)-phenyl-ethyl]-4-/so-butyl-1 ,5-dihydro-pyrrol-2-one as dark yellow oil (15.5 g).

FTIR (neat): 3319, 2959, 1751 , 1166 cm ¹ .

¹ H NMR (CDCI ₃ , 200 MHz): δ 0.86-0.94 (t, 3H), 0.96-0.99 (t, 3H), 1.34-1.38 (d, 2H), 1.49-1.53 (d, 1 H), 1.75-1.85 (m, 1 H), 2.24-2.27 (d, 2H), 4.27-4.30 (q, 1 H), 5.17 (s, 1 H), 5.88 (s, 1 H), 7.26-7.37 (m, 5H).

MS (El): C ₁₆ H ₂ iN0 ₂ : 259.0; [M+H] ⁺ : 260.30.

Example 8: Hydrogenation of 5-hydroxy-1-[(S)-phenyl-ethyl]-4-/ ^' sobutyl-1 ,5-dihydro- pyrrol-2-one

5-Hydroxy-1-[(S)-phenyl-ethyl]-4-/sobutyl-1 ,5-dihydro-pyrrol-2-one (5.0 g) was dissolved in methanol (100 mL) into a Parr autoclave reactor followed by addition of 0.5 g of 50 % wet palladium-on-carbon (Pd/C) at 10 % catalyst loading. Reactor was purged with hydrogen gas twice and then 3 kg hydrogen pressure was maintained. Reaction was monitored by TLC [Chloroform: methanol (9:1)]. After complete consumption of starting material, the reaction was stopped.

After completion of reaction, the reaction mixture was filtered to separate the Pd/C and filtrate was concentrated under vacuum to obtain a semi solid material, which was suspended in cyclohexane (300 ml_) and stirred overnight to yield 3.5 g of 3- isobutyl-4-((S)-1 '-phenylethylamino) butanoic acid as off-white solid obtained after vacuum filtration.

FTIR (KBr): 3435, 2955, 1552, 1399, 702 cm ¹ .

¹ H NMR (CDCI ₃ , 200 MHz): δ 0.73-076 (t, 3H), 0.81-0.85 (t, 3H), 0.92-1.06 (m, 2H) 1.46-1.52 (m, 1 H), 1.71-1.77 (m, 2H), 2.12-2.39 (m, 2H), 2.45-2.55 (m, 2H), 2.74-2.77 (d, 1 H) 4.06-4.10 (q, 1 H), 7.31-7.56 (m, 5H); ¹³ C NMR (CDCI ₃ , 50 MHz): 20.8, 22.2, 22.6, 24.9, 31.4, 43.3, 44.0, 52.1 , 58.8, 127.5, 128.5, 129.2, 137.9, 179.5;

MS (El): C ₁₆ H ₂ 5N0 ₂ : 263.4; [M+H] ⁺ : 264.5.

Example 9: Synthesis of 5-hydroxy-1-[(S -phenyl-ethyl]-4-n-methyl-1 ,5-dihydro-pyrrol-2- one

5-Hydroxy-4-n-methyl-5 - -furan-2-one (5.0 g) was dissolved in /so-propanol (100 mL) and (S)-a-methyl benzyl amine (5.4 g) was added to it at room temperature. The mixture was stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC, 1 :1 ethyl acetate:hexane), the solvent was evaporated under reduced pressure in a rotary evaporator to afford 5-hydroxy-1-[(S -phenyl-ethyl]-4-n-methyl-1 ,5-dihydro- pyrrol-2-one as dark yellow oil (10.5 g).

FTIR (neat): 3319, 2959, 1751 , 1166 cm ^'1 .

MS (El): C ₁₃ H ₁₅ N0 ₂ : 217.0; [M+H] ⁺ : 217.90. Example 10: Hydrogenation of 5-hydroxy-1-[(S -phenyl-ethyl]-4-methyl-1 ,5-dihydro- pyrrol-2-one

A solution of 5-hydroxy-1-[(S phenyl-ethyl]-4-methyl-1 ,5-dihydro-pyrrol-2-one (10.5 g) in /so-propanol (100 mL) was charged into a Parr autoclave reactor followed by addition of 50 % wet palladium-on-carbon (Pd/C) (1.0g). Reactor was purged with hydrogen gas twice and 3 kg hydrogen pressure was maintained. Reaction was monitored by TLC [Chloroform: methanol (9:1)]. After complete consumption of starting material, the reaction was stopped. In the reaction, diastereomers are separated, (S)-3-methyl-4-((S)-1'-phenylethylamino)butanoic acid precipitates out from the reaction media and (R)-3-methyl-4-((S)-1'-phenylethylamino)butanoic acid remains dissolved in the reaction media.

After completion of reaction, the reaction mixture was filtered and filtrate was concentrated under vacuum to obtain a semi solid material, which was suspended in cyclohexane (300 mL) and stirred overnight to yield 3.0 g of (R)-3-methyl-4-((S)-1'- phenylethylamino)butanoic acid as a off-white solid obtained after vacuum filtration.

Filtered cake contained Pd/C and (S)-3-methyl-4-((S)-1'-phenylethylamino)butanoic acid which was suspended in methanol and stirred for 20 min to dissolve (S)-3- methyl-4-((S)-1'-phenylethylamino)butanoic acid. Pd/C was separated by filtration. Filtrate was concentrated under vacuum to obtain 4.1 g of (S)-3-methyl-4-((S)-1 - phenylethylamino)butanoic acid as a white solid. (S)-3-methyl-4-((S)-1 '-phenylethylamino)butanoic acid:

FTIR (KBr pellets): 2960, 1623, 1547 cm ¹ ;

MS (El): C ₁₃ H ₁₉ N0 ₂ : 221.17; [M+H] ⁺ : 221.90 (ff)-3-methyl-4-((S)-1 '-phenylethylamino)butanoic acid:

FTIR (KBr pellets): 2956, 1619, 1549, 1400 cm ¹ ;

MS (El): Ci ₃ H ₁₉ N0 ₂ : 221.17; [M+H] ⁺ : 221.95.

Example 11 : Synthesis of 5-hydroxy-1-[(S)-phenyl-ethyl]-4-ethyl-1 ,5-dihydro-pyrrol-2- one

(S)-cr-Methyl benzyl amine (5.2 g) was added slowly into a solution of 5-hydroxy-4-etf?y/- 5H-furan-2-one (5.0 g) in /so-propanol (100 mL) and stirred for 1 h at room temperature. After completion of the reaction (monitored by TLC, 1 :1 ethyl acetate:hexane), solvent was evaporated under reduced pressure in a rotary evaporator to afford 5-hydroxy-1- [(S phenyl-ethyl]-4-ethyl-1 ,5-dihydro-pyrrol-2-one as dark yellow oil (10.5 g).

FTIR (neat): 3319, 2959, 1751 , 1166 cm ¹ .

MS (El): C ₁₄ H ₁₇ N0 ₂ : 231.13; [M+H] ⁺ : 231.90.

Example 12: Hydrogenation of 5-hydroxy-1-[(S)-phenyl-ethyl]-4-ethyl-1 ,5-dihydro- pyrrol-2-one

A solution of 5-hydroxy-1-[(S)-phenyl-ethyl]-4-ethyl-1 ,5-dihydro-pyrrol-2-one (15.0 g) was dissolved in / ^' so-propanol (100 mL) and transferred into a Parr autoclave reactor followed by addition of 50 % wet palladium-on-carbon (Pd/C) (1.5gm). Reactor was purged with hydrogen gas twice and 3 kg hydrogen pressure was maintained. Reaction was monitored by TLC [Chloroform: methanol (9:1)]. After complete consumption of starting material, the reaction was stopped. In the reaction, diastereomers are separated, (S)-3-ethyl-4-((S)-1'-phenylethylamino)butanoic acid precipitates out from the reaction media and (R)-3-ethyl-4-((S)-1 '- phenylethylamino)butanoic acid remains dissolved in the reaction media.

After completion of reaction, the reaction mixture was filtered and filtrate was concentrated under vacuum to obtain a semi solid material, which was suspended in cyclohexane (300 mL) and stirred overnight to yield 4.0 g of (R)-3-ethyI-4-((S)-1 '- phenylethylamino)butanoic acid as a off-white solid obtained after vacuum filtration.

Filtered cake contains Pd/C and (S)-3-ethyl-4-((S)-1'-phenylethylamino)butanoic acid which was suspended in methanol and stirred for 20 min to dissolve (S)-3-ethyl-4- ((S)-1'-phenylethylamino)butanoic acid. Pd/C was separated by filtration. Filtrate was concentrated under vacuum to obtain 5.1 g of (S)-3-ethyl-4-((S)-1 - phenylethylamino)butanoic acid.

(S)-3-ethyl-4-((S)-1 '-phenylethylamino)butanoic acid:

FTIR (KBr pellets): 2960, 1623, 1547 cm ^"1 ;

MS (El): C1 H21NO2: 235.17; [M+H] ⁺ : 236.05

(ff)-3-ethyl-4-((S)-1 '-phenylethylamino)butanoic acid:

FTIR (KBr pellets): 2956, 1619, 1549, 1400 cm ¹ ;

MS (El): C14H21NO2: 235.17; [M+H] ⁺ : 236.50. Example 13: Hydrogenation of 5-hydroxy-1-[(S)-phenyl-ethyl]-4-n-propyl-1 ,5- dihydro-pyrrol-2-one with Pd/C

A solution of 5-hydroxy-1-[(S)-phenyl-ethyl]-4-n-methyl-1 ,5-dihydro-pyrrol-2-one (10.5 g) in methanol (100 mL) was charged into a Parr autoclave followed by addition of 50 % wet palladium-on-carbon (Pd/C) (1.0g). Reactor was purged with hydrogen gas twice and 3 kg hydrogen pressure was maintained. Reaction was monitored by TLC [chloroform: methanol (9:1)]. After complete consumption of starting material, the reaction was stopped.

After completion of reaction, the reaction mixture was filtered and filtrate was concentrated under vacuum to obtain a semi solid material, which was suspended in cyclohexane (300 ml_) and stirred overnight to yield 7.5 g of diastereomeric mixture of 3-propyl-4-((S)-1 '-phenylethylamino)butanoic acid a off-white solid obtained after vacuum filtration. 3-propyl-4-((S)-1 '-phenylethylamino)butanoic acid

FTIR (KBr pellets): 2960, 1623, 1547 cm ^'1 ;

¹ H NMR (CDCI ₃ , 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, 2H), 2.75-2.78 (d, 1 H), 4.12-4.17 (q, 1 H), 7.35-7.42 (m, 3H), 7.47-7.51 (m, 2H); MS (El): C ₁₅ H ₂₃ N0 ₂ : 249.17; [M+H] ⁺ : 250.20

Example 14: Co-crystal formation of diastereomeric mixture of 3-propyl-4-((S)-1 '- phenylethylamino)butanoic acid with (S>-1 ,1'-bi-2-naphthol (S)-1 ,1'-Bi-2-naphthol (3.45 g) was added into the solution of 3-propyl-4-((S)-1 '- phenylethylamino)butanoic acid (3.0 g) in methanol (50 mL) and stirred for 1 h at 50 °C; during which time solid precipitate came out from the reaction mixture. Reaction mixture was allowed to cool to room temperature and filtered under reduced pressure to obtain 4.55 g of the complex. Figure 1. PXRD of co-crystal of 3-propyl-4- ((S)-1 '-phenylethylamino)butanoic acid: (SJ-1 ,1 '-bi-2-naphthol

FTIR Spectra KBr (cm-1): 3449, 3059, 2960, 2458, 1620, 1595, 1557, 1504, 1458, 1431 , 1397, 1324, 1307, 1275, 1139, 1123, 818, 750, 709 Powder X-ray diffraction 2Θ 8.41 , 9.38, 10.32, 12.16, 15.52, 15.51 , 17.84, 17.95, 19.16, 20.37, 21.74, 22.55, 24.44, 25.65, 28.40, 29.15, 29.69, 31.31 , 33.54, 34.40 and 35.43 ±0.2.

Specific optical rotation (c=1 in methanol) at 25°C: -17.73. DSC (10 °C/min): Peak at 189.23 °C.

Example 15: Separation of (S)-1 , 1 '-bi-2-naphthol from (RS)-1 ,1'-bi-2-naphthol via formation of binary/ternary co-crystal with 3-alkyl-4-(1'-phenylethylamino)butanoic acid. 3-alkyl-4-(1'-phenylethylamino)butanoic acid (0.385 moles) was dissolved in methanol (five volumes) and (RS)-1 ,1'-bi-2-naphthol (0.35 moles, i.e. 100 g) was added to it at room temperature. The mixture was stirred at 50 °C for 2 hour, during which time solid precipitate came out from the reaction mixture. Reaction mixture was allowed to cool to room temperature and filtered under reduced pressure to obtain solid co-crystal.

Co-crystal was suspended in methanol (five volumes) and stirred at 50 °C for 2 h. After which reaction mixture was cooled to room temperature and filtered under reduced pressure to obtain pure solid co-crystal.

Pure co-crystal was suspended in a biphasic mixture of ethyl acetate (2.5 volumes) and 1Λ/ hydrochloric acid (2.5 volumes) and stirred for 30 to 45 min to decompose the complex. Aqueous phase was washed with 2 volumes of ethyl acetate. Organic phases were mixed together and washed with brine, followed by drying over sodium sulfate. Solvent was evaporated under vacuum to obtain optically pure (S)-1 ,1'-bi-2-naphthol which was analyzed for ee on chiral chromatography.

Chiral chromatographic conditions for (S)-1.1'-bi-2-naphthol

Retention time for (S)-1, 1'-bi-2-naphthol : 17.77 min

Retention time for (R)-1, 1'-bi-2-naphthol : 20.64 min

Instrument HPLC using a Shimadzu LC 2010 system equipped Pump, Injector, UV detector and Recorder Column: Chiral Pak IA, 4.6mm x 250mm, 5μιη, column oven temperature 40 °C Detector. UV at 230 nm.

Mobile phase: n-hexane (94) :n-butanol (5) : ethanol (1): trifluoroacetic acid (0.3 mL) Flow rate: 1 mL min

Injection volume: 20 μΙ.

Yield and enantiomeric excess of (S)-1 ,1'-bi-naphthol using various 3-alkyl-4-(1'- phenylethylamino)butanoic acids for co-crystal formation during resolution of (RS)-1 ,1 - bi-naphthol are tabulated below in table 4:

Table 4

* Data represented for antipode of (S)-1 ,1'-bi-naphthol. Example 16: Separation of (S)-1, 1'-bi-2-naphthol from (RS)-1 ,1'-bi-2-naphthol via formation co-crystal with diastereomeric mixture of 3-propyl-4-((S)-1'- phenylethylamino)butanoic acid.

3-propyl-4-((S)-1'-phenylethylamino)butanoic acid (250.0 g) was dissolved in methanol (1200 mL) and (RS)-1 ,1'-bi-2-naphthol (260.0 g) was added to it at room temperature. The mixture was stirred at 50 °C for 2 hour, during which time solid precipitate came out from the reaction mixture. Reaction mixture was allowed to cool to room temperature and filtered under reduced pressure to obtain 235 g of solid co-crystal.

Co-crystal (235 g) was suspended in methanol (700 mL) and stirred at 50 °C for 2 h. After which reaction mixture was cooled to room temperature and filtered under reduced pressure to obtain 210 g of solid co-crystal.

Co-crystal (210 g) was suspended in the biphasic mixture of ethyl acetate (500 mL) and 1Λ/ hydrochloric acid (500 mL) and stirred for 30 to 45 min to decompose the complex. Aqueous phase was washed with 200 mL ethyl acetate. Organic phases were mixed together and washed with brine, followed by drying over sodium sulfate. Solvent was evaporated under vacuum to obtain optically pure (S)-1 ,1'-bi-2-naphthol (100 g) having 99 % ee by chiral HPLC analysis. The acid aqueous solution which contained hydrochloride salt of 3-propyl-4-((S)-1 '- phenylethylamino)butanoic acid was neutralized with dilute solution of sodium bicarbonate to recover the 3-propyl-4-((S)-1 '-phenylethylamino)butanoic acid (85 g), which on HPLC analysis shows that the diseteromeric ratio is 1 :1. Material balance shows that co-crystal consists of three component i.e (S)-1 , 1 '-bi-2- naphthol : (S)-3-propyl-4-((S)-1'-phenylethylamino)butanoic acid : (R)-3-propyl-4-((S)-1 '- phenylethylamino)butanoic acid in molar ratio 1 :0.5:0.5.

DSC (10 °C/min): Peak at 189.23 °C.

Powder X-ray diffraction 2Θ 8.41 , 9.38, 10.32, 12.16, 15.52, 15.51 , 17.84, 17.95, 19.16, 20.37, 21.74, 22.55, 24.44, 25.65, 28.40, 29.15, 29.69, 31.31 , 33.54, 34.40 and 35.43±0.2

Chiral chromatographic conditions for (S)-1.1'-bi-2-naphthol

Retention time for (S)-1, 1'-bi-2-naphthol : 17.77 min Retention time for (R)-1, 1'-bi-2-naphthol : 20.64 min

Instalment HPLC using a Shimadzu LC 2010 system equipped Pump, Injector, UV detector and Recorder

Column: Chiral Pak IA, 4.6mm x 250mm, 5μητι, column oven temperature 40 °C Detector. UV at 230 nm.

Mobile phase: n-hexane (94) :n-butanol (5) : ethanol (1 ): trifluoroacetic acid (0.3 mL) Flow rate: 1 mL/min

Injection volume: 20 μΙ. Chromatographic conditions for 3-propyl-4-((S)-1 '-phenylethylamino)butanoic acid Instrument. HPLC using a Shimadzu LC 2010 system equipped Pump, Injector, UV detector and Recorder

Column: Inertsil Sil column (4.6mm x 250mm, 5μπι), column oven temperature 25 °C Detector. UV at 210 nm.

Mobile phase: n-hexane (94): ethanol (05): trifluoroacetic acid (0.2): triethylamine (0.1)

Flow rate: 1 mL/min

Injection volume: 20 μΙ.

Retention time for (S)- 3-propyl-4-((S)-V-pheny\et y\amino)butanoic ac/cM 9.90 min Retention time for (R)-3-propyl-4-((S) '-pheny\ethy\amino)butanoic acid: 22.18 min