FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
"A PROCESS FOR THE PREPARATION OF LASOFOXIFENE TARTRATE


Glcnmark Generics Limited an Indian Company, registered under the Indian company's Act 1957 and having its
registered oiYice at
Glcnmark House.
MIX.) Corporate Bldg. Wing -A.
B.D. Sawant Marg, Chakala, Andheri (Last). Mumbai 400 099
he following specification describes the nature of the invention


FIELD OF INVENTION
|0001| The present invention relates to solid state chemistry of l-(2-[4-(6-
methoxy-3,4-dihydronaphthalene-l-yl) phenoxyjethyl)pyrrolidine. a process for its preparation and its use as an intermediate in the synthesis of lasofoxifene. BACKGROUND OF THE INVENTION
[0002] l-(2-[4-(6-methoxy-3,4-dihydronaphthalene-l-yl) phenoxy"|ethyl)
pyrrolidine, as shown below.

Formula IV is a key intermediate in the preparation of lasofoxifene and its salts. Lasofoxifene D-tartrate, (-)-(5R, 6S)-6-Phenyl-5-['4-[2-(l-pyrrolidinyl)ethoxy]phcnyl]- 5.6,7.8 tctrahydronaphthalen-2-ol D tartrate, represented by the structural formula.

is an estrogen agonist. FABLYN® (lasofoxifene) functions as selective estrogen
receptor modulator (SERM) for the treatment of osteoporosis in post-menopausal women
at increased risk of fracture and has received approval from the European Commission
(EC). FABLYN® was submitted for approval in Europe in January 2008.
|0003] Lasofoxifene is disclosed in U.S. Patent No. RE 39558 while its tartrate
salt is disclosed in U.S. Patent No. 5948809. U.S. RE39558 describes a process of preparing ]-(2-[4-(6-Methoxy-3, 4-dihydronaphthalene-l -yl) phenoxy] ethyl) pyrrolidine, which is obtained as an oil, by the reaction of l-[2-(4-bromophenoxy) ethyl)J pyrrolidine and 6-methoxy-l-tetralone with butyl lithium (Bul.i) in tetrahydrofuran (THF) and in the presence of cesium chloride.
[0004] Polymorphic forms occur where the same composition of matter
crystallizes in a different lattice arrangement resulting in, for example, different
15 JUL 2009

thermodynamic properties and stabilities specific to the particular polymorph form. Thus. polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks.
|0005j When a compound is in its solid form, it allows ease of handling
particularly when said compound participates in a multiple step synthesis. Herein, the preparation and isolation of l-(2-[4-(6-methoxy-3, 4-dihydronaphthalene-l-yl) phenoxy| ethyl) pyrrolidine in its solid and crystalline state subsequently contributes to the facile synthesis of lasofoxifenc.
SUMMARY OF THE INVENTION.
[0006] The present invention relates to l-(2-[4-(6-metho.\y-3. 4-
dihydronaphthalene-1-yl) phenoxy] ethyl) pyrrolidine in solid form.
[0007] The present invention relates to l-(2-|4-(6-Methoxy-3. 4-
dihydronaphthalene-1-yl) phenoxy] ethyl) pyrrolidine in a solid crystalline state having
characteristic
(i) XRD peaks at 9.13, 10.5. 15.78, 17.04. 18.06. 18.37. 19.01. 21.01.
21.13, 21.86, 22.87 and 23.43 ±0.2 "2'fhcta (ii) IR at 554.9, 602. 622.7, 648, 674, 747.7, 790.8. 809.9. 817.1. 845.1. 879.7, 905.3. 953, 974, 1046. 1119.2, 1162.9, 1152. 1175.7. 1204.4. 1249.5. 1280.5, 1303, 1330, 1356.6, 1374.3. 1556. 1455.7. 1491.1. 1508.4, 1566.5, 1608.4. 1751.2. 1881.5, 2080.4. 2773.4, 2809.9. . 2920.4, 2940.5, 3031.9. 3444.4 (iii) DSC onset of 71.17°C±2.0°C and peak 74.35°C+2.0°C (iv) 'HNMR (400MHz, CDC13): § 7.26-7.23 (d, J- 10.4 I I/z. 211). 6.96-
6.90 (t, 3H), 6.76 (s. 111), 6.64-6.62 (d, 11.2 Hz,l II). 5.92-5.89 (t, 111).
4.16-4.12 (t, 2H), 3.78 (s, 311) 2.94-2.90 (t, 2H), 2.83-2.78 (t, 2H). 2.64
(s. 4H). 2.39-2.32 (m. 2H) 1.81(s, 4H) m/z=350 (M+Il): melting point
range between 71 °C and 75°C.
The aforementioned characteristics are as substantially in accordance with figs. 1 to 4,
[0008] The present invention provides a process for the preparation of a solid
crystalline form of l-(2-[4-(6-methoxy-3, 4-dihydronaphthalene-l-yl)phenoxy| ethyl)
1 5 JUL 2009

pyrrolidine, a compound of formula IV. comprising, reacting 6-methoxy-l-tetralone with Grignard reagent of l-[2-(4-bromophenoxy) ethyl)] pyrrolidine, a compound of formula HI


Formula IV comprising:
a) reacting a compound of formula II with Mg to form a Grignard reagent ol formula III

Formula II Formula III
b) reacting the compound of formula III with 6-mcthoxy-l-tctralone in the presence of a
solvent to obtain a crystalline solid l-(2-[4-(6-methoxy-3,4 dihydronaphthalene-1-y!)
phenoxy] ethyl) pyrrolidine, a compound of formula IV.
[0010] The present invention provides a process for the preparation of, Cis-6-

Formula 1 comprising:
phenyl-5-|4-(2-pyrrolidin-l-yl-ethoxy) phenyl"]-5. 6, 7. 8-tetrahydronaphthalene-2-ol). compound of formula I.
1 5 JUL 2009




a) halogenating l-(2-|4-(6-methoxy-3.4 dihydronaphthalene-1-yl) phcnoxy| ethyl) pyrrolidine ,a compound of formula IV. prepared as described above.
where X is a halogen selected from chlorine, bromine, iodine.
b) phenylating the compound of formula V to obtain l-(2-[4-(6-Methoxy-2-phenyl-3. 4-
dihydronaphthalene-1-yl) phenoxy| ethyl) pyrrolidine hydrochloride a compound of
formula VI,

Formula VI wherein the phenylating reagent is selected from phenyl boronic acid, phenyl boronic acid glycol ester, phenyl boron di-halogen like phenyl boron dichloride, phenyl boron dibromide and phenyl boron diiodide.
c) reducing the compound of formula VI to obtain Cis-l-(2-[4-(6-Methoxy-2-phcnyl-l.
2. 3. 4-tetrahydronaphthalene-l-yl) phenoxy] ethyl) pyrrolidine, a compound of formula
VII.
to obtain a compound of formula V,

Formula IV
Formula V
Formula VII

1 5 JUL 2009

wherein the reducing agent is selected from palladium/C (Pd/C). palladium hydroxide and Raney Ni.
d) reacting the compound of formula Vll with an acid to form cis-6-phenyl-5-|4-(2-pyrrolidin-1-yl-ethoxy) phenyl]-5. 6. 7, 8-tetrahydronaphthalene-2-ol). a compound of formula I

Formula I wherein the acid is selected from 48% hydrobromic acid, acetic acid in hydrobromic acid and boron tribromide in methylene chloride.
[0011 ] e) optionally converting the compound of formula I to its corresponding
pharmaceutically acceptable salt/s.The present invention provides crystalline lasofoxifene tartrate characterized by an X-ray Diffraction (XRD) spectrum, which is substantially in accordance with Fig. 5 and a Differential Scanning Caloriinctric (DSC) thermogram, which is substantially in accordance with Fig. 6.
10012] The present invention provides crystalline lasofoxifene tartrate further
characterized by Infrared (IR) spectrograph, which is substantially in accordance with Fig. 7; and a Thermogravimetric Analysis (TGA) thermogram, which is substantially in accordance with Fig. 8.
[0013] The present invention provides crystalline lasofoxifene tartrate further
characterized having crystalline particles with a specific surface area from about 4 m"/g to
about 7m7g, as measured by Brunauer-Hmmett-Teller (Bin) method.
[0014] The present invention provides crystalline lasofoxifene tartrate particles,
wherein 90% of the particles have a particle size less than 750 urn
[0015] The present invention provides crystalline lasofoxifene tartrate having a
Hake morphology as observed by SF1M. which is substantially in accordance with Fig 9.
10016] The present invention provides crystalline lasofoxifene tartrate having
tapped bulk density ranging from about 0.26g/ml to about 0.56g/ml and untapped bulk density ranging from about 0.22g/ml to about 0.52g/ml.
15 JUL 2009

BRIEF DESCRIPTION OF DRAWINGS
10017] Fig. 1 represents an XRD diffractogram of l-(2-[4-(6-methoxy-3. 4-
dihydronaphthalene-1-yl) phenoxy] ethyl) pyrrolidine.
[0018] Fig. 2 represents an IR spectra of l-(2-[4-(6-methoxy-3. 4-
dihydronaphthalene-1-yl) phenoxy] ethyl) pyrrolidine.
|0019] Fig. 3 represents a DSC thermogram of l-(2-[4-(6-methoxy-3. 4-
dihydronaphthalene-1-yi) phenoxy] ethyl) pyrrolidine.
|0020] Fig. 4 represents an NMR spectra of l-(2-[4-(6-mcthoxy-3, 4-
dihydronaphthalene-1-yl) phenoxy] ethyl) pyrrolidine.
(0021] Fig. 5 represents XRD diffractogram of Lasofoxifene Tartrate.
[0022] Fig.6 represents DSC thermogram of Lasofoxifene Tartrate.
|0023] Fig. 7 represents IR spectra of Lasofoxifene fartrate.
|0024| Fig. 8 represents TGA of Lasofoxifene Tartrate.
[0025] Fig. 9 represents SEM of Lasofoxifene Tartrate.
DETAILED DESCRIPTION OF INVENTION.
[0026] The present invention relates to solid state chemistry of l-(2-[4-(6-
methoxy-3,4-dihydronaphthalene-l-yl)phcnoxy]ethyl)pyrrolidine. which is a useful intermediate for preparing lasofoxifene.
[0027] The present invention relates to solid crystalline l-(2-[4-(6-methoxy-3,
4-dihydronaphthalene-l-yl) phenoxy] ethyl) pyrrolidine, a compound of formula IV.

Formula IV
characterized by XRD peaks at 9.13. 10.5. 15.78. 17.04, 18.06. 18.37. 19.01. 21.01.
21.13, 21.86, 22.87 and 23.43 ±0.2 °2 theta. which is substantially in accordance with
Fig.l.
[0028] X-Ray Powder were performed on ARI. (scanting) X-Ray
Diffractometer model XPERT-PRO (PANalvtical) scanning parameters start position
|°2Th.| 2.01 and End position [°2Th.] 49.98.
7 15 JUL 2009

|0029] The compound of' formula IV is characterized by a DSC onset of
71.17°C±2.0°C and peak 74.35°C±2.0°C, which substantially in accordance with Fig.3.
[0030| The compound of formula IV is also characterized by IR peaks at
554.9. 602, 622.7. 648. 674. 747.7, 790.8. 809.9. 817.1. 845.1. 879.7. 905.3. 953. 974. 1046. 1119.2. 1162.9. 1152. 1175.7, 1204.4. 1249.5. 1280.5. 1303. 1330. 1356.6. 1374.3. 1556, 1455.7, 1491.1. 1508.4, 1566.5, 1608.4, 1751.2. 1881.5. 2080.4. 2773.4. 2809.9. 2920.4, 2940.5, 3031.9, 3444.4, which substantially in accordance with Fig.2. The compound of formula IV exhibits an 'll NMR (400MHz, CDC13): § 7.26-7.23 (d. J-10.4 H/z, 2H), 6.96-6.90 (t, 311), 6.76 (s, 1H). 6.64-6.62 (d. 11.2 IIz.lII). 5.92-5.89 (t. 111). 4.16-4.12 (t, 211), 3.78 (s, 311) 2.94-2.90 (t. 211). 2.83-2.78 (t, 211), 2.64 (s. 4H), 2.39-2.32 (m. 211) 1.81 (s, 4H); m/z-350 (M+ II): melting point range between 71 °C and 75°C. . which substantially in accordance with l;ig.4.
|0031 j The present invention provides a process for the preparation of
l-(2-|4-(6-Methoxy-3, 4-dihydronaphthalene-l-yl)phenoxy]ethyl)pyrrolidine comprising reacting 6-methoxy-l-tctralone with a Grignard reagent.

[0032] The process above further comprises adding 6-mcthoxy-l-tetralone in
the desired solvent to a Grignard reagent. The Grignard reagent is prepared by reacting 1-
|2-(4-bromophenoxy) ethyl)| pyrrolidine with Mg metal in a solvent.
100331 The solvents for carrying out the reaction are selected from ether
solvents such as tctrahydrofuran. diethyl ether and diisopropyl ether. Preferably the
solvent is tctrahydrofuran (TIIF).
[0034| The reaction is carried out at about room temperature and the reaction
time can vary from between about 12 hours to about 20 hours. Preferably, the reaction
transpires between about 14 hours to about 16 hours. Once the reaction is completed.
water is added to the reaction mass and filtered. The filtrate is acidified.
[0035| The extraneous materials or impurities were removed by extraction and
the aqueous layer is basified.
|0036] The product from the basic solution is extracted by a solvent and the
solvent is concentrated. The residue obtained is taken up in diisopropyl ether and stirred
8
1 5 JUL 2009

for about 30 min to about 10 hours. Preferably for about 4 hours to about 6 hours.
whereby l-(2-[4-(6-methoxy-3, 4-dihydronaphthalene-l-yl)phenoxy|ethyl)pyrrolidine is
obtained as a crystalline solid having a melting range between 71°C to 75°C.
|0037) The compound of formula II. l-(2-|4-bromophenoxy) ethyl) |
pyrrolidine, can be made by any method known in the art. Illustratively, it is described in
US3321483, which is included by reference herein, in its entirety,
[0038] Further, the present invention provides the conversion of the solid
crystalline l-(2-[4-(6-Mcthoxy-3,4-dihydronaphthalene-l-yl)phenoxy]ethyl) pyrrolidine
to lasofoxifene by processes known in the art. Illustratively, it is described in U.S. Patent
No. RE39558. which is included by reference herein, in its entirety.
(0039] The present invention provides a process for the preparation of cis-6-
phenyl-5-[4-(2-pyrrolidin-l-yl-ethoxy) phenyl]-5, 6, 7, 8-tetrahydronaphthalene-2-ol). a
compound of formula I.

Formula I
comprising:
a) halogenating l-(2-|4-(6-Methoxy-3.4-dihydronaphthalene-l-yl)phenoxy|ethyl)
Formula IV
to obtain a compound of formula V.
15 JUL 2009
pyrrolidine a compound of formula IV, wherein compound of formula IV is prepared as described above.



ormula V

Formula VI wherein the phenylating reagent is selected from, phenyl boronie acid, phenyl boronie acid glycol ester, phenyl boron di-halogcn like phenyl boron dichloride, phenyl boron dibromide and phenyl boron diiodide. Preferably the phenylating reagent is phenyl boronie acid.
e) reducing the compound of formula VI to obtain Cis-l-(2-|4-(6-Methoxy-2-phcnyl-l. 2, 3, 4-tetrahydronaphthalcne-l-yl) phenoxy] ethyl) pyrrolidine, a compound of formula VII,

Formula VII wherein the reducing agent is selected from palladium/C, palladium hydroxide and Ranev nickel. Preferably the reducing agent is palladium/C.
d) reacting the compound of formula VII with an acid to form cis-6-pheny1-5-[4-(2-pyrrolidin-1-yl-ethoxy) phenyl |-5, 6, 7. 8-tetrahydronaphthalene-2-ol . a compound of formula I
15 JUL 2009


formula I
wherein the acid is selected from 48% hydrobromic acid, acetic acid in hydrobromic acid and boron tribromidc in methylene chloride. Preferably the acid is 48% hydrobromic acid.
e) optionally, converting the compound of formula 1 to its corresponding pharmaceutically acceptable salt/s.
[0032] The present invention provides a process for the preparation of a
pharmaceutically acceptable salt of lasofoxifene comprising reacting a pharmaceutically acceptable acid with lasofoxifene in solution.
10033] Suitable pharmaceutically acceptable acids which can be used include, but
are not limited to: inorganic acids such as phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid; and organic acids such as acetic acid, tartaric acid, oxalic acid, and the like. Preferably the acid is tartaric acid.
|0034] Optionally, the acid is dissolved in a solvent before adding it to the solution
of lasofoxifene free base.
|0035] The solvent used for the dissolution of lasofoxifene and the acid may be
the same, or different solvents may be used.
[0036] Suitable solvents in which the acid addition salt oi' lasofoxifene can be
prepared include but are not limited to: 1, 4-dioxane: aprotic solvents such as dimethyl
formamide (DMF), dimethyl sulfoxide (DMSO) and mixtures thereof.
[0037] Polymorphism is the occurrence of different crystalline forms of a single
compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with

predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry.
[0038] The present invention provides crystalline lasofoxifene tartrate characterized
by an X-ray Diffraction (XRD) spectrum, which is substantially in accordance with Fig. 5 and an Infrared (IR) spectrograph, which is substantially in accordance with Fig. 7 [0039] The present invention provides crystalline lasofoxifene tartrate further characterized by a Differential Scanning Calorimetric (DSC) thermogram with an endothermic curve at about 171.23"C with an onset at about 163.15 "C and endset at about 1 76.67°C, which is substantially in accordance with Fig. 6.
[0040] The present invention provides crystalline lasofoxifene tartrate further
characterized by Thermogravimetric Analysis (TGA) thermogram showing a weight loss
of about 0.6876% up to 100°C, which is substantially in accordance with Fig. 8.
[0041] The specific surface area of an active pharmaceutical ingredient may be
affected by various factors. It is recognized that there is an inverse relationship between surface area and particle size; where the smaller the particle size, the higher the surface area. Whereupon, the available surface area for drug dissolution correlates to the rate of dissolution and solubility. A greater surface area enhances both the solubility and the rate of dissolution of a drug, which in turn, may improve its bioavailability and potentially its toxicity profiles.
[0042| Thus, there is a need in the art to prepare active pharmaceutical
ingredients, such as lasofoxifene tartrate, with a high surface area to obtain formulations with greater bioavailability, and to compensate for any loss of surface area before formulation.
[0043J Specific surface area is defined in units of square meters per gram (m"/g).It
is usually measured by nitrogen absorption analysis. In this analysis, nitrogen is absorbed on the surface of the substance. The amount of the absorbed nitrogen (as measured during the absorption or the subsequent desorption process) is related to the surface area via a formula known as the BFT formula.
[0044] The present invention further characterizes crystalline particles of
lasofoxifene tartrate having a specific surface area from about 4 m"7g to about 7m7g. as

measured by Brunauer-Emmett-Teller (BET) method. Preferably, the surface area is 5.21 m2/g.
[0045] In the field of pharmaceutical formulation, it is notable that particle size
plays a pivotal role in the solubility properties of an API. like lasofoxifene tartrate. Particle size reduction techniques are commonly employed to increase a compound's solubility. Particle size reduction increases the surface area of the solid phase that is in contact with the liquid medium. However, particle size reduction cannot alter the solubility of the compound in a solvent, which is a thermodynamic quantity. At instances where the rate of dissolution of a poorly soluble drug is the rate limiting factor in its rate of absorption by the body, it is recognized that the bioavailability of such drugs may be enhanced when administration occurs in a finely divided state, further, particle size can also affect how freely crystals or a powdered form of a drug will How past each other, which in turn, has consequences in the production process of pharmaceutical products containing the drug.
[0046) In one aspect, the present invention provides crystalline lasofoxifene
tartrate characterized by Malvern Mastersizer 2000® that demonstrates that the material comprises irregularly shaped particles with 90% of the particles having a particle size of less than 750 urn, 50% of the particles having a particle size of 250 um and 10% of the particles having a particle size of 15um.
(0047] The present invention provides crystalline lasofoxifene tartrate having a
Hake morphology as observed by SEM. which is substantially in accordance with fig. 9.
[0048] Tapped bulk density is defined as the maximum packing density of a
powder (or blend of powders) achieved under the influence of well defined, externally applied forces. Thus factors include particle size distribution, true density, particle shape and cohesiveness due to surface forces including moisture affect the minimum packed volume the minimum packed volume. Flow properties and its compressibility can be predicted by tap density of the material and play a vital role in the overall tableting process, which requires that loose powders be compacted into a durable solid form with the correct mechanical strength, porosity and dissolution characteristics. These parameters are also important in the formation of oral suspensions, which ideally contain particles of high bulk density, enabling even dispersion of the particles throughout the suspension after shaking and before consumption.

[0049] In one aspect the present invention provides crystalline lasofoxifene
tartrate having tapped bulk density ranging from about Q.26a/ml to about 0.56g ml and
untapped bulk density ranging from about 0.22 g/ml to about 0.52 g/ml.
Preferably, the tapped density is 0.36 g/ml and the untapped density is 0.32 g/ml.
[0050] The present invention provides a lasofoxifene free base or a
pharmaceutically acceptable salt thereof; preferably the tartrate salt obtained using the process of the described herein, may have a residual solvent content that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines. The guideline solvent level depends on the type of solvent but is not more than about 5000 ppm, or about 4000 ppm, or about 3000 ppm.
(0051] The present invention provides lasofoxifene tartrate, obtained by the
process disclosed herein, having less than about 1500 parts per million (ppm) C1.4 alcohols such as methanol, ethanol, isopropanol, preferably less than about 1000 ppm; less than about 1000 ppm ethyl acetate, preferably less than about 500 ppm; less than about 1000 ppm tetrahydrofuran, preferably less than about 500 ppm: less than about 1000 ppm dichloromethane, preferably less than about 500 ppm.
[0052] While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended within the scope of the present invention.
[0053] The following examples are provided to enable one skilled in the art to
practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLE
|0054] EXAMPLE 1
Preparation of l-{2-|4-(6-Methoxy-3, 4-dihydronalphthalene-l-yl) phenoxy] ethyl)
pyrrolidine, Formula IV:
A solution of 140g of 6-methoxy-l-tetralone in 400ml of tetrahydrofuran (THE) was added to the Grignard reagent prepared from 200g of l-[2-(4-bromophenoxy) ethyl)] pyrrolidine and 23g of Mg in 1000ml of TEIE. The reaction mixture was stirred for 16 hours and then water (100ml) was added. The reaction mass was filtered through Celite® and filtrate was concentrated. To the residue, water (1000ml) was added and acidified with 2.5N HCl to bring the pH below 2. The acidic solution was extracted with diisopropyl ether (1000ml). The aqueous layer was basified using 10% sodium hydroxide. The basic solution was extracted with methylene chloride (1000ml) and was dried over anhydrous sodium sulphate. The methylene dichloride layer was concentrated. Residue obtained was taken up in diisopropyl ether (1000ml) and stirred for 5 hours. The solid was filtered obtain the target product of 164g of l-{2-[4-(6-Methoxy-3. 4-dihydronaphthalene-1-yl) phenoxy] ethyl) pyrrolidine, a compound of formula IV. Light brown color solid
'H NMR (400MHZ, CDC13):
§ 7.26-7.23 (d, J=10.4 H/z, 2H), 6.96-6.90 (t, 3H), 6.76 (s, 1H), 6.64-6.62 (d, 11.2 Hz.lH), 5.92-5.89 (t, 1H), 4.16-4.12 (t, 2H), 3.78 (s. 3H) 2.94-2.90 (t, 2H). 2.83-2.78 (t. 2H). 2.64 (s. 4H), 2.39-2.32 (m, 2H) 1.81(s, 4H) m/z-350 (M+H): m.p=71-75°C. XRD peaks:
9.13, 10.5, 15.78, 17.04, 18.06, 18.37, 19.01, 21.01. 21.13, 21.86, 22.87 and 23.43 ±0.2 ° 2Theta FT-IR (KBr):
554.9, 602. 622.7, 648, 674, 747.7, 790.8, 809.9, 817.1, 845.1, 879.7. 905.3. 953. 974. 1046. 1119.2, 1162.9, 1152, 1175.7, 1204.4. 1249.5. 1280.5. 1303. 1330. 1356.6. 1374.3. 1556. 1455.7, 1491.1. 1508.4, 1566.5, 1608.4. 1751.2(br). 1881.5. 2080.4. 2773.4. 2809.9. 2920.4, 2940.5, 3031.9, 3444.4 DSC: Onset of 71.17°C±2.0°C and peak 74.35°C±2.0° C

FEATURES:
The invention is particularly represented as:
A] A solid crystalline form of l-(2-[4-(6-methoxy-3, 4-dihydronaphthalene-l -yl)phenoxy]cthyl) pyrrolidine , compound of formula IV.

Formula IV
having characteristics, which are substantially in accordance with Figures 1 to 4. respectively:
(i) XRD peaks at 9.13, 10.5. 15.78. 17.04. 18.06, 18.37. 19.01.21.01.21.13.
21.86. 22.87 and 23.43 4:0.2 °2Thcta (ii) 1R at 554.9, 602, 622.7, 648, 674, 747.7. 790.8. 809.9. 817.1. 845.1. 879.7. 905.3,953,974, 1046. 1119.2, 1162.9. 1152, 1175.7, 1204.4, 1249.5. 1280.5, 1303, 1330, 1356.6, 1374.3. 1556, 1455.7. 1491.1. 15084. 1566.5. 1608.4. 1751.2, 1881.5, 2080.4, 2773.4. 2809.9. 2920.4. 2940.5. 3031.9. 3444.4 (iii) DSC onset of 71.17°C±2.0°C and peak 74.35°C i 2.0°C
(iv) 'H NMR (400MHz. CDC13): § 7.26-7.23 (d, .1=10.4 H/z. 211), 6.96-6.90 (t. 3H), 6.76 (s, 1H), 6.64-6.62 (d. 1 1.2 IIz.lH), 5.92-5.89 (t. Ill), 4.16-4.12 (t, 211), 3.78 (s, 311) 2.94-2.90 (t, 211), 2.83-2.78 (t. 211), 2.64 (s, 4H). 2.39-2,32 (m, 211) 1.81(s. 4H) m/z-350 (M+H): melting point range between 71 °C and 75°C.
B| A process for the preparation of a solid crystalline form of l-(2-|4-(6-methoxy-3. 4-dihydronaphthalene-l-yl) phenoxy] ethyl) pyrrolidine as defined in 'A' comprising reacting 6-methoxy-l-tetralone with a Grignard reagent of l-|2-(4-bromophenoxy) ethyl)] pyrrolidine, a compound of formula J J J.

Formula III
in the presence of a solvent.
C] The process as defined in TV. wherein the solvent is selected from ether solvents like tetrahydrofuran, diisopropyl ether and diethyl ether
D| The process as defined in 'B\ wherein the reaction temperature is between about 0"C to about reflux temperature of the solvent.
H) The process as defined in 'C wherein the reaction temperature is between about 20 "C to about 30 °C.
1'J A process for the preparation of Cis-6-phenyl-5-[4-(2-pyrrolidin-l-yl~ethoxy) phenyl J-5, 6, 7, 8-tetrahydronaphthalene-2-ol, a compound of formula 1.

Formula IV
to obtain a compound ol' formula V.

Formula V
1 5 JUL 2009
Formula I comprising: a) halogenating a compound of formula IV. prepared as described in A to H.


where X is a halogen selected from chlorine, bromine, iodine;
b) phenylating the compound of formula V to obtain l-(2-[4-(6-methoxy-2-phenyl-3,
4-dihydronaphthalene-l-yl) phenoxy] ethyl) pyrrolidine hydrochloride, a compound of formula VI,

Formula VI
wherein the phenylating agent is selected from phenyl boronic acid, phenyl boronic acid glycol ester, phenyl boron di-halogen like phenyl boron dichloridc. phenyl boron dibromidc and phenyl boron diiodide;
c) reducing the compound of formula VI to obtain ci.s-l-(2-[4-(6-mcthoxy-2-phenyl-
1, 2, 3, 4-tetrahydronaphthalenc-l-yl) phenoxy] ethyl) pyrrolidine, a compound of formula VII,

Formula VII
wherein the reducing agents can be selected from palladium/C, palladium hydroxide and Raney nickel;

Formula I
d) reacting the compound of formula VII with an acid to obtain a compound of formula 1

wherein the acid is selected from 48% hydrobromic acid, acetic acid in hydrobromic acid and boron tribromide in methylene chloride;
e) Optionally converting the compound of formula 1 to its corresponding pharmaceutically acceptable salt/s.
H] A crystalline lasolbxifcne tartrate characterized by an X-ray Diffraction (XRD) spectrum, which is substantially in accordance with Fig. 5; and a Differential Scanning Calorimetric (DSC) thermogram, which is substantially in accordance with Fig. 6.
IJ The compound as described in "H having characteristic Infrared
(IR)spectrograph, which is substantially in accordance with Fig. 7: and a Thermogravimetric Analysis (TGA) thermogram, which is substantially in accordance with Fig 8.
J] Crystalline particles of lasofoxifene tartrate having a specific surface area from
about 4 m7g to about 7m'/g, as measured by Brunauer-Emmctt-feller (BHT) method.
K] The compound as described in 'II, which are particles, wherein 90% of the particles have a particle size less than 750 p.m.
L| The compound, as described in 'IT, having aflake morphology as observed by SFM, which is substantially in accordance with Fig 9.
M| The compound as described in 'IT, having a tapped bulk density ranging from about 0.26g/ml to about 0.56g/ml and untapped bulk density of about 0.22g/ml to about 0.52g/ml.
Dated this Fourteenth (14th ) day of July, 2009

(Signed)
Dr. MADHAVI KARN1K
DEPUTY GENERAL MANAGER - IPM
GLENMARK GENERICS LIMITED