FORM 2
THE PATENTS ACT, 1970
(39 of 1970) &
The Patents Rules, 2003
COMPLETE SPECIFICATION (See section 10; rule 13)
1. Title of the invention.- CRYSTALLINE FORM OF
DIMETHYL (3, 3-DIFLUORO-2-OXOHEPTYL)
PHOSPHONATE AND PROCESS FOR PREPARATION
THEREOF
2. Applicant(s)
(a) NAME : LUPIN LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : 159 CST Road, Kalina, Santacruz (East),
Mumbai-400 098, State of Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Technical field of the invention
The present invention relates to crystalline form of "dimethyl (3, 3-difluoro-2-oxoheptyl) phosphonate (phosphonate compound)".The present invention also provides a simple cost effective process for obtaining said intermediate in solid form with superior purity and high yield.
Back ground of the invention
Lubiprostone is 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxo-octahydro -cyclo-penta-[b]pyran-5-yl]-heptanoic acid (Drugs of the Future, 2004, 29(4); 336-341). Lubiprostone is a bicyclic fatty acid of El type prostaglandin derivative. It is marketed in USA as Amitiza® and used for the treatment of idiopathic chronic constipation and irritable bowel syndrome. The use of lubiprostone softens the stool, increases motility, and promotes spontaneous bowel movements (SBM).

US patent 5,284,858 describes the novel 13,14-dihydro-15-keto prostaglandins E and the use for treatment and prevention of several types of ulcers, such as duodenal ulcer and gastric ulcer.
US 7,355,064 discloses an improved process for preparation of 15-ketoprostaglandin E derivative. According to this patent, the deprotection of protected

hydroxyl group required in manufacturing a 15-keto-prostaglandin derivative and was carried out in the presence of a phosphoric acid compound.
US 5,229,529 provides a method of preparing α,β-unsaturated ketolactones, which are useful for production of prostaglandins having one or more halogen substituent(s). More particularly prostaglandins having one or more halogen substituent(s) at the 16 or 17 position in high yield. The said patent describes dimethyl (2-oxoalkyl) phosphonate compound having one or more halogen substituents as starting material, and was reacted with a bicycle lactone aldehyde in the presence of an alkali metal hydride and a zinc compound.
US 5,468,880 describes a method of producing α,β unsaturated ketones by reacting aldehyde with 2-oxoalkyl phosphonate, wherein the reaction was carried out in the presence of a base and a zinc compound.
US 6,414,016 provides an anti-constipation composition containing a halogenated bicyclic compound as an active ingredient in a ratio of bicyclic/monocyclic structure of at least 1:1.

The prior art methods for preparation of Lubiprostone, explain the phosphonate compound is a key intermediate and isolated in oily form.

The prior art methods for preparation of phosphonate compound suffer from drawbacks such as the phosphonate compound is in oily form, which is difficult to handle on a commercial scale and leads to loss of yield of Lubiprostone.
It is evident from prior art published patents that the crucial feature in the manufacture of Lubiprostone is the synthesis of the key intermediate "dimethyl (3, 3-difluoro-2-oxoheptyl) phosphonate" and the processes reported in the literature for its synthesis are not very attractive in view of cost, use of undesirable toxic reagents and eco-hazardous operations.
Thus, this invention provides an improved, highly cost effective, and operation friendly crystalline form of "dimethyl (3, 3-difluoro-2-oxoheptyl) phosphonate" and process for preparation thereof.
Object of the invention
The objective of the present invention is;
1) to provide the crystalline form of "dimethyl (3, 3-difluoro-2-oxoheptyl)
phosphonate (phosphonate compound)", which is easy to handle;
2) to obtain phosphonate compound with high purity and better yield;
3) to overcome the previous problems associated with the preparation of phosphonate compound;
4) to provide a viable process for preparation of phosphonate compound, which will be easy and cost effective to implement on industrial scale;
5) to avoid column chromatography purification in the process for preparation of phosphonate compound.

Description of drawings
Figure 1: illustrates X-ray powder diffraction pattern of crystalline phosphonate.
Figure 2: illustrates IR spectrum of crystalline phosphonate.
Summary of the invention
The present invention relates to crystalline form ofdimethyl (3, 3-difluoro-2-oxoheptyl) phosphonate(phosphonate).The present invention also provides a simple and cost effective process for obtaining the phosphonate compound in superior purity and high yield on a large scale.
Detail description of the invention
The present invention provides a process for preparation of phosphonate compound of formula (I), which comprises of; i) treating diethyl oxalate with n-butyl magnesium bromide under a suitable organic solvent; ii) adding of diethyl amino sulphur triflouride to ethyl-2-oxohexonoate; iii) treating dimethyl methyl phosphonate to ethyl-2,2-difluoro hexanoate in presence of a base; iv) charge alcoholic solvent and DM water to the crude oil obtained from step iii.
The process of present invention is depicted in the following scheme:


The compound (3, 3-difluoro-2-oxoheptyl)-phosphonate of formula (I) is a key side chain intermediate of Lubiprostone.The compound of formula is used in the synthesis of(4R,5R)-4-((E)-4,4-difluoro-3-oxooct-l-en-l-yl)-2-oxohexahydro-2H-cycIopenta[b]furan-5-yl[l,1'-biphenyl]-4-carboxylate(Lubi-I),which further converted to Lubipro stone by the methods known in state of the art.
In one embodiment of the invention, the present invention provides solid crystalline phosphonate compound (compound of formula(I)), characterized by

XRPD (X-ray powder diffractogram) which comprises of peaks expressed as 2theta at 11.3,12.5,13.3,13.9,18.9, 21.8 and 24.1(+) 0.2°. The XRPD of solid crystalline form of phosphonate is depicted in figure 1.
The 1R spectrum of said crystalline form of phosphonate compound is depicted in figure 2 which exhibits major peaks at 3420.2, 3283.5, 2964.5, 2935.2, 2876.1, 1465.5, 1449.0, 1394.2, 1384.1, 1351.3, 1269.1, 12.31.4, 1197.1, 1180.8, 1158.13, 1116.67, 1092.2, 1055.7, 1038.8, 1011.4, 922.7, 896.2, 865.9, 826.3, 806.4, 751.0, 734.6, 692.7, 595.3, 556.5, 524.1 & 430.7 cm-1.The solid crystalline form of phosphonate compound melts at 55.°C to 57.9°C.
In one aspect of the present invention is to obtain the key side chain intermediate phosphonate compound of formula (I).
The organic solvents employed in step (i) and (iii) are tetrahydrofuran (THF), dimethyl ether and diethyl ether. Preferably THF is employed.
The organic solvents employed in step (ii) are dichloromethane, trichloromethane and trichloroethane. Preferably dichloromethane is employed.
The alcoholic solvent employed in step (iv) are methanol, ethanol, n-butanol and isopropyl alcohol. Preferably isopropyl alcohol is employed.
The base employed in step (iv) are n-butyllithium, n-hexyllithium, sodium hydride and lithium hydride. Preferably n-hexyllithium is employed.
The product is isolated by conventional techniques known in prior art such as extraction, concentration, centrifugation, filtration and drying.
The invention is further illustrated by way of following examples which should not be construed as limiting to the scope of the invention.

The X-ray diffraction patterns were measured using Philips X'Pertpro machine with following measurement parameters:
Scan axis: Gonio
Step size: 0.008°
Scan type: Continuous
Divergence slit size: 0.2393
Anode material: Cu
K-Alpha l[A°j: 1.54060
K-Alpha 2[A0]: 1.54443
K-Beta[A0]: 1.39225
Scan: 3.49 to 39.9 theta
Spinning: Yes
Measurement temperature: 25°C
The below examplesare intended to illustrate specific embodiment of the invention and is not intended to limit the scope of the specification, including the claims, in any manner.
Example-1
Preparation of ethyl-2-oxo-hexanoate (compound of formula (III)):
a) Preparation of Grignard reagent:
IHF (500 mL) followed by n-butyl bromide(112.6 gm) was charged to the round bottom flask containing Magnesium metal (24.65 gm)under nitrogen atmosphere at

40-45°C.A pinch of iodine was also added to the reaction mixture. The reaction mass was cooled to 25-30°C with stirring.
b) Preparation of ethyl-2-oxo-hexanoate:
The above Grignard reagent mixture was added to the RBF containing diethyl oxalate(100 gm) at -78oC under nitrogen atmosphere. The reaction was stirred and maintained at the same temperature for 120-150 minutes. The reaction was monitored by Gas Chromatography (GC-method).The reaction mass quenched with 20 % dilute hydrochloride solution (500 mL)by adjusting the pH to 1 to 1.5.The reaction mass stirred for 30 minutes and the pH was adjusted to 7 to 7.5 with 10% sodium bicarbonate(500 mL) solution. The mixture was extracted with dichloromethane(lOOOmL), concentrated and dried under vacuum to obtain thick oil. (Percentage yield: 97%)
Example-2
Preparation of ethyl-2, 2-difluorohexanoate (compound of formula (IV)):
In a round bottom flask containing ethyl-2-oxohexanoate(100 gm), dichloromethane(300 mL) was charged to it under Nitrogen atmosphere at 0-5°C.The diethyl amino sulphur trifluoride(101.5 gm) was added drop wise to the round bottom flask under Nitrogen atmosphere at 0-5°C.The reaction mass was stirred and maintained at the same temperature for 120-130 minutes. The reaction was monitored by Gas Chromatography (GC-method).The reaction mass was quenched with aqueous 10% ammonium chloride (1000 mL) and extracted with dichloromethane. The organic layer was concentrated and dried under vacuum to obtain thick oil. (Percentage yield: 92.9%)

Example-3
Preparation of dimethyl (3, 3-difluoro-2-oxoheptyl)-phosphonate (compound of formula (I)):
In a round bottom flask containing the phosphonate compound (82.56 gm.), THF(350 mL) was charged at -78°C under nitrogen atmosphere. The n-hexyl lithium(76.41 gm.) was added drop wise to the above solution. The reaction mass was stirred at the same temperature for 120-130 minutes. The reaction was monitored by Gas Chromatography (GC-method). The reaction mass was quenched with dilute hydrochloride and the pH was adjusted to 5.5-6.0 DM water was added to the above reaction mixture and extracted with dichloromethane (l000mL). The extraction was repeated for 3-4 times and the organic layer was washed with water. The obtained organic layer was concentrated and dried under vacuum to obtain thick oil.
The obtained thick oil (dimethyl (3, 3-difluoro-2-oxoheptyl)-phosphonate) was charged with isopropyl alcohol (l00mL). The solution was stirred for 30 minutes.DM water (200mL) was added to the solution and was cooled to 0 to 5°C.The above solution was maintained at the same temperature for 240 minutes. The obtained crystalline solid was filtered and dried under vacuum (percentage yield:78.5%).
Example-4
Preparation of Lubi-I:


a) Preparation of Corey's Aldehyde: In a 1L round bottom flak, 132gm of Dess-Martin pertodinane and 1200ml dichloromethane was charged and waskept stirring under nitrogen atmosphere at 0-5°C. The lOOgm of Corey's lactone was charged in above reaction massand stirred for 90 minutes at room temperature. The reaction was monitored by Gas Chromatography (GC-method). After completion of reaction, the reaction mass was quenched with a solution containing 118gms of sodium bicarbonate and 104gms of sodium thiosulfate in 1500ml of water. The reaction mass was extracted with 500ml of dichloromethane. The dichloromethane layer was separated and dried over sodium sulfate and this dried organic layer used for next stage.
b) Preparation of LUBI-I: In a 500ml round bottom flak, 95.28gm of dimethyl (3,3-difluoro-2-oxoheptyl)-phosphonate and 500ml of THF was charged and was maintained under nitrogen atmosphere at 0-5°C. The 47.72gm of potassium tert. butoxide was slowly added to above reaction mass at the same temperature. The reaction mass was stirred for 10-15 minutes and anhydrous zinc chloride was added.The reaction temperature was slowly raised to 25-30°C and was stirred for 120 minutes. The corey's aldehyde in dichloromethane layer as prepared in step a) was slowly added to the reaction mass and was maintained for 24 hours. The reaction was monitored by Gas Chromatography (GC-method). After completion of reaction, the reaction mass was quenched with acetic acid. The layers were separated and extracted with dichloromethane and concentrated to get the thick oil. The thick oilwas recrystallized from methanol. The titled product was dried under vacuum (Percentage of yield: 69.3%).
The intermediate Lubi-I will be further processed to prepare lubiprostone with available methods in state of the art.


WE CLAIM:
1. A crystalline compound of formula (I),
having powder X-ray diffraction pattern with peaks at 11.3,12.5, 13.3,18.9,21.8 and 24.1 +0.2° 2θ.
2. A crystalline compound of formula (I), having melting point of 55.5oC to 57.9°C.
3. A crystalline compound of formula (I),having particular infrared absorption bands at 3420,3283,2964,1449,1197 and 865cm-1 on the IR spectrum.
4A crystalline compound of formula (I) of claim 1, having an X-ray diffraction pattern substantially similar to FIG. 1.
5. A crystalline compound of formula (I) of claim 1, having an IR spectrum pattern substantially similar to FIG. 2.
6. A process for isolation of compound of formula (l),said process comprising i)adding the liquid form of compound of formula(I) into an alcohol; ii) stirring if necessary; iii)adding the water;iv)isolating the crystalline solid compound of formula
(I).
7. The process of claim 7, wherein the alcohol is methanol, ethanol, n-butanol and isopropyl alcohol.
8. The process of claim 7, wherein the alcohol is isopropyl alcohol.

9. The process of claim 7, wherein the purity of the compound of formula (I) obtained
is more than 95%.
10. The use of crystalline compound of formula (I), in the synthesis of Lubiprostone.