FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"PROCESS FOR PREPARATION OF DISTRONTIUM 5-[BIS (2-OXIDO-2-OXOETHYL) AMINO]-4-CYANO-3-(2-OXIDO-2-OXOETHYL)THIOPHENE-2-CARBOXYLATE'"
Enaltec Labs Pvt. Ltd. an Indian Company, having its Registered Office at 17thFloor, Kesar Solitaire, Pfot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
]. The following specification particularly describes the invention and the manner in which it is to be performed.

PROCESS FOR PREPARATION OF DISTRONTIUM 5-[BIS (2-OXIDO-2-
OXOETHYL)AMlNO]-4-CYANO-3-(2-OXIDO-2-OXOETHYL)THIOPHENE-
2-CARBOXYLATE
FIELD OF THE INVENTION
The present invention relates to processes for producing distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyI) thiophene-2-carboxylate comprising reacting a compound of formula V with strontium hydroxide.
BACKGROUND OF THE INVENTION
Distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate is known from U.S Patent No. 5,128.367 and is represented by compound of formula I.

Distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate have valuable therapeutic and pharmacological properties, especially remarkable anti-osteoporosis properties, as a result of which they can be used as medicaments especially in the treatment of bone diseases. They can also be used in the treatment of cutaneous and vascular ageing, hepatic diseases and dental diseases.
Distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate is indicated for the treatment of osteoporosis in postmenopausal women to reduce the risk of vertebral and hip fractures.

U.S Patent No. 5,128,367 discloses processes for the preparation of distrontium 5-[bis
(2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-
carboxylate compound of formula I, which comprises hydrolysis of tetra ethyl ester compound of formula II in an aqueous alcoholic medium at reflux temperature.

Formula II
U.S Patent No. 7,214,805 discloses processes for the preparation of distrontium 5-[bis
(2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-
carboxylate compound of formula I, which comprises reacting a compound of formula III with strontium hydroxide in an amount greater than or equal to 2 mole per mole of compound of formula III in water at reflux temperature.

Wherein R and R, which may be the same or different, each represent a linear or branched (C1-C6) alkyl group.
U.S Patent Publication No. 2009/0082578 discloses processes for the preparation of ■ distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate compound of formula I, which comprises reacting a compound of formula III with sodium hydroxide or potassium hydroxide in water or in a mixture of water and an organic solvent, at a temperature from 0° to 100°C.

U.S Patent Publication No. 2009/0214631 discloses processes for the preparation of distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoefhyl) thiophene-2-carboxylate compound of formula I, which comprises reacting a tetraester compound of formula IV, wherein R, R1, R2, and R3 are independently a linear or branched C1-C6 alkyl group or a substituted or unsubstituted C3-C12 cyclic group, in the presence of a lithium base and in a solvent with an inorganic acid salt of strontium.

Formula IV
SUMMARY OF THE INVENTION
The present invention encompasses processes for producing distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate comprising reacting a compound of formula V with strontium hydroxide.

Formula V
wherein R5, R6, R7 and R8, which may be the same or different, each represent independently a -NR9R10 or -OR12 with the proviso that at least one of the R5, R6, R7

and Rg is -NR9R10. R9 R10 and R12 are independently hydrogen, linear or branched C1-C6 alkyl group or a substituted or unsubstituted C3-C12 cyclic group.
Another embodiment of the present invention encompasses processes for producing a compound of formula V comprising reacting compound of formula VI with ammonia.

Formula VI
wherein R5, R6, R7, and R8', which may be the same or different, each represent independently -OR12. R12 is independently hydrogen, linear or branched C1-C6 alkyl group or a substituted or unsubstituted C3-C12 cyclic group.
Another embodiment of the present invention encompasses a compound of formula V

Formula V
wherein R5, R6, R7 and R8, which may be the same or different, each represent independently a -NR9R10 or -ORi2 with the proviso that at least one of the R5, R6, R7 and R8 is -NR9R10. R9,R10 and R12 are independently hydrogen, linear or branched C1-C6 alkyl group or a substituted or unsubstituted C3-C12 cyclic group.

Another embodiment of the present invention encompasses processes for producing a compound of formula V comprising reacting a compound of formula VII with 2-bromoalkylamide.

wherein X is R7 or Rg.
In one embodiment, the preparation of distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate from a compound of formula V can be carried out via formation of a lithium salt of formula VIII.

Formula VII DETAILED DESCRIPTION OF THE INVENTION
The starting compound of formula V may include following compounds:
I. 3-(2-Amino-2-oxoethyl)-5-(bis (2-amino 2-oxoethyl) amino)-4-cyanothiophene-
2-carboxamide.
II. Ethyl 2-(5-(bis (2-amino-2-oxoethyl) amino)-2-carbamoyl-4-cyanothiophen-3-yl)
acetate.
III. Ethyl 5-(bis (2-amino-2-oxoethyl) amino)-4-cyano-3-(2-ethoxy-2-oxoethyl)
thiophene-2-carboxylate.

IV. Ethyl 5-((2-amino-2-oxoethyl) (2-ethoxy-2-oxoethyl)-4-cyano-3-(2-ethoxy-2-
oxoethyl) thiophen -2-carboxylate.
V. Diethyl 2, 2'-(5-carbamoyl-3-cyano-4-(2-ethoxy-2-oxoethyl) thiophen-2-
ylazanediyl) diacetate.
VI. Ethyl 3-(2-amino-2-oxoethyl)-5-(bis (2-ethoxy-2-oxoethyl) amino)-4-
cyanothiophene-2-carboxylate.
VII. Ethyl 2-((2-amino-2-oxoethyl) (4-(2-amino-2-oxoethyl)-5-carbamoyl-3-
cyanothiophen-2-yl) amino) acetate.
VIII. Ethyl 2-(5-((2-amino-2-oxoethyl) (2-ethoxy-2-oxoethyl) amino)-2-carbamoyl-4-
cyanothiophen-3-yl) acetate.
IX. Methyl 2-(5-(bis (2-amino-2-oxoethyl) amino)-2-carbamoyl-4-cyanothiophen-3-
yl) acetate.
X. Methyl 5-(bis (2-amino-2-oxoethyl) amino)-4-cyano-3-(2-ethoxy-2-oxoethyl)
thiophene-2-carboxylate.
XI. Methyl 5-((2-amino-2-oxoethyl) (2-ethoxy-2-oxoethyl)-4-cyano-3-(2-ethoxy-2-
oxoethyl) thiophen -2-carboxylate.
XII. Dimethyl 2, 2'-(5-carbamoyl-3-cyano-4-(2-ethoxy-2-oxoethyl) thiophen-2-
ylazanediyl) diacetate.
XIII. Methyl 3-(2-amino-2-oxoethyl)-5-(bis (2-ethoxy-2-oxoethyl) amino)-4-cyanothiophene-2-carboxylate.
XIV. Methyl 2-((2-amino-2-oxoethyl) (4-(2-amino-2-oxoethyl)-5-carbamoyl-3-cyanothiophen-2-yl) amino) acetate.
XV. Methyl 2-((2-amino-2-oxoethyl) (4-(2-amino-2-oxoethyl)-5-carbamoyl-3-
cyanothiophen-2-yl) amino) acetate.
XVI. Methyl 2-(5-((2-amino-2-oxoethyl) (2-ethoxy-2-oxoethyl) amino)-2-carbamoyl-
4-cyanothiophen-3-yl) acetate.
XVII. Methyl 2-(5-((2-amino-2-oxoethyl) (2-methoxy-2-oxoethyl) amino)-2-
carbamoyl-4-cyanothiophen-3-yl) acetate.
XVIII. Methyl 3-(2-amino-2-oxoethyl)-5-(bis (2-methoxy-2-oxoethyl) amino)-4-cyanothiophene-2-carboxylate.
XIX. Dimethyl 2, 2'-(5-carbamoyl-3-cyano-4-(2-methoxy-2-oxoethyl) thiophen-2-
ylazanediyl) diacetate.
XX. Methyl 5-((2-amino-2-oxoethyl) (2-methoxy-2-oxoethyl)-4-cyano-3-(2-ethoxy-2- oxoethyl) thiophen -2-carboxylate.

XXI. Methyl 5-(bis (2-amino-2-oxoethyl) amino)-4-cyano-3-(2-methoxy-2-oxoethyl)
thiophene-2-carboxylate.
XXII. Ethyl 2-(5-((2-amino-2-oxoethyl) (2-methoxy-2-oxoethyl) amino)-2-carbamoyl-4-cyanothiophen-3-yl) acetate.
XXIII. Ethyl 3-(2-amino-2-oxoethyl)-5-(bis (2-methoxy-2-oxoethyl) amino)-4-cyanothiophene-2-carboxylate.
XXIV. Ethyl 5-(bis (2-amino-2-oxoethyl) amino)-4-cyano-3-(2-rnethoxy-2-oxoethyl) thiophene-2-carboxylate.
The reaction of a compound of formula V with strontium hydroxide is carried out in organic solvent or water.
Examples of organic solvent include alcohols, ethers or ketones.
Examples of alcohols solvent include methanol, ethanol, propanoi, isopropanol, n-butanol or isobutanol.
Examples of ethers solvent include tetrahydrofuran or dioxane.
Examples of ketones solvent include acetone, methyl ethyl ketone, methyl butyl ketone, methyl isobutyl ketone, dipropyl ketone diisopropyl ketone, diethyl ketone. methyl propyl ketone, methyl isopropyl ketone, ethyl propyl ketone or ethyl isopropyl ketone.
The organic solvent or water is present in an amount of 1 to 25 volumes of a compound of formula V.
The amount of strontium hydroxide used in the reaction is from the range of 1 mole to 5.0 moles per mole of compound of formula V.
The reaction of a compound of formula V with strontium hydroxide is carried out at a temperature in the range of 25°C to 100°C.

The reaction of a compound of formula V with strontium hydroxide is carried out for a time period for 30 minutes to 6 hours.
The distrontium 5-[bis <2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxi.do-2-oxoethyl) thiophene-2-carboxylate may be isolated by the steps of filtration, centrifugation, washing, drying and combination thereof.
The distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate may be dried at a temperature in the range of 30°C to 50°C under reduced pressure.
The compound of formula VI is described in the literature such as M.Wierzbicki et al. Bull. Soc. Chim. (1975) pages 1786-92.
The reaction of a compound of formula VI with ammonia may be carried out in the presence of ammonium sulfate.
The reaction of a compound of formula VI with ammoma is carried out in alcoholic
solvents.
Examples of alcoholic solvents include methanol, ethanol, propanol, isopropanol, butanol. isobutanol or mixture(s) thereof.
The reaction of a compound of formula VI with ammonia is carried out at a temperature in the range of 0°C to 20°C for a time period of 5 hours to 15 hours.
The reaction of a compound of formula VII with 2-bromoalkylamide may be carried out in the presence of inorganic base in an alcoholic solvents.
Examples of inorganic base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride or sodium methoxide.
Examples of alcoholic solvents include methanol, ethanol n-propanol, isopropanol, n-butanol. isobutanol, n-pentanol or isopentanol.

The reaction of a compound of formula VII with 2-bromoalkylamide may be carried out at a temperature in the range of 20°C to 70°C for a time period of 2 hours to 8 hours.
The preparation of distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate from a compound of formula V may be carried out by hydrolysis of a compound of formula V with lithium hydroxide to obtain a compound of formula VII, followed by its reaction with inorganic acid salts of strontium.
The hydrolysis of a compound of formula V with lithium hydroxide is carried out in alcoholic or ether solvents.
Example of inorganic acid salts of strontium is strontium chloride.
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
EXAMPLE 1: Preparation of 3-(2-amino-2-oxoethyl)-5-(bis (2-amino 2-oxoethyl) amino)-4-cyanothiophene-2-carboxamide
A solution of ethyl 5-(bis (2-ethoxy-2-oxoethyl) amino)-4-cyano-3-(2-ethoxy-2-oxoethyl) thiophene-2-carboxylate (90 gm) in methanol (2000 ml) was added ammonium sulfate (20 gm) and ammonia gas was bubbled for 10 hours at 0-5°C and resulting by-products was filtered and clear filtrate was concentrated under reduced pressure to obtain a residue. The residue was crystallized in isopropyl alcohol solvent at 20-30°C. Yield: 90 gm

Example 2: Preparation of distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyI) thiophene-2-carboxylate
3-(2-Amino-2-oxoethyl)-5-(bis (2-amino 2-oxoethyl) amino)-4-cyanothiophene-2-carboxamide (101 gm wet weight) was added into a solution of strontium hydroxide (135.6 gm) in water (1100 ml) at 25-30°C. The resulting reaction mixture was refluxed for 7 hours and resulting solids were filtered at 25-30°C. washed with a mixture of isopropyl alcohol (4 ml) and hot water (200 ml) and dried under reduced pressure at 30-35°C for 24 hours. Yield: 135 gm Purity: 99.5% (By HPLC).

WE CLAIM:
1. A process for producing distrontium 5-[bis (2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-carboxylate comprising reacting a compound of formula V with strontium hydroxide.

Formula V
wherein R5, R6, R7 and R8, which may be the same or different, each represent independently a -NR9R10 or -OR12 with the proviso that at least one of the R5, R6, R7 and R8 is -NR9R10. R9, R10 and R12 are independently hydrogen, linear or branched C1-C6 alkyl group or a substituted or unsubstituted C3-C12 cyclic group.
2. A process for producing a compound of formula V comprising reacting compound of formula VI with ammonia.

Formula VI
Wherein R5, R6, R7 and R8, which may be the same or different, each represent independently -OR12- R12 is independently hydrogen, linear or branched C1-C6 alkyl group or a substituted or unsubstituted C3-C12 cyclic group.

3. A compound of formula V

Formula V
wherein R5, R6, R7 and Rg. which may be the same or different, each represent independently a -NR9R10 or -OR12 with the proviso that at least one of the R5, R6, R7 and Rg is -NR9R10. R9 R10 and R12 are independently hydrogen, linear or branched C1-C6 alkyl group or a substituted or unsubstituted C3-C12 cyclic group.
4. A process for producing a compound of formula V comprising reacting a compound of formula VII with 2-bromoalkylamide.

5. The process according to claim no. 1 wherein the preparation of distrontium 5-[bis
(2-oxido-2-oxoethyl) amino]-4-cyano-3-(2-oxido-2-oxoethyl) thiophene-2-
carboxylate from a compound of formula V is carried out via the formation of a lithium salt of the compound of structural formula VIII.


6. The compound of formula V include following compounds:
I. 3-(2-Ammo-2-oxoethyl)-5-(bis (2-amino 2-oxoethyl) amino)~4-
cyanothiophene-2-carboxamide.
II. Ethyl 2-(5-(bis (2-amino-2-oxoethyl) amino)-2-carbamoyl-4-
cyanothiophen-3-yl) acetate.
III. Ethyl 5-(bis (2-amino-2-oxoethyl) amino)-4-cyano-3-(2-ethoxy-2-
oxoethyl) thiophene-2-carboxylate.
IV. Ethyl 5-((2-amino-2-oxoethyl) (2-ethoxy-2-oxoethyl)-4-cyano-3-(2-
ethoxy-2- oxoethyl) thiophen -2-carboxylate.
V. Diethyl 2. 2'-(5-carbamoyl-3-cyano-4-(2-ethoxy-2-oxoethyl) thiophen-2-
ylazanediyl) diacetate.
VI. Ethyl 3-(2-amino-2-oxoethyl)-5-(bis (2-ethoxy-2-oxoethyl) amino)-4-
cyanothi ophene-2-carboxy1ate.
VII. Ethyl 2-((2-amino-2-oxoethyl) (4-(2-amino-2-oxoethyl)-5-carbamoyl-3-
cyanothiophen-2-yl) amino) acetate.
VIII. Ethyl 2-(5-((2-amino-2-oxoethyl) (2-ethoxy-2-oxoethyl) amino)-2-carbamoyl-4-cyanothiophen-3-yl) acetate. IX. Methyl 2-(5-(bis (2-amino-2-oxoethyl) amino)-2-carbamoyl-4-
cyanothiophen-3-yl) acetate.
X. Methyl 5-(bis (2-amino-2-oxoethyl) amino)-4-cyano-3-(2-ethoxy-2-
oxoethyl) thiophene-2-carboxylate.
XI. Methyl 5-((2-amino-2-oxoethyl) (2-ethoxy-2-oxoethyl)-4-cyano-3-(2-
ethoxy-2- oxoethyl) thiophen -2-carboxylate.
XII. Dimethyl 2. 2,-(5-carbamoyl-3-cyano-4-(2-ethoxy-2-oxoethyl) thiophen-2-ylazanediyl) diacetate.

XIII. Methyl 3-(2-amino-2-oxoethyl)-5-(bis (2-ethoxy-2-oxoerhyl) amino)-4-cyanothiophene-2-carboxylate.
XIV. Methyl 2-((2-amino-2oxoethyl) (4-(2-amino-2-oxoethyl)-5-carbamoyl-3-cyanothiophen-2-yl) amino) acetate.
XV. Methyl 2-((2-amino-2-oxoethyl) (4-(2-amino-2-oxoethyl)-5-carbamoyl-3-
cyanothiophen-2-yl) amino) acetate.
XVI. Methyl 2-(5-((2-amino-2-oxoethyl) (2-ethoxy-2-oxoefhyl) amino)-2-
carbamoyl-4-cyanothiophen-3-yl) acetate.
XVII. Methyl 2-(5-((2-amino-2-oxoethyl) (2-methoxy-2-oxoethyl) amino)-2-
carbamoyl-4-cyanothiophen-3-yl) acetate.
XVIII. Methyl 3-(2-amino-2-oxoethyI)-5-(bis (2-methoxy-2-oxoethyl) amino)-4-cyanothiophene-2-carboxylate,
XIX. Dimethyl 2, 2'-(5-carbamoyl-3-cyano-4-(2-methoxy-2-oxoethyl)
thiophen-2-ylazanediyl) diacetate.
XX. Methyl 5-((2~amino-2-oxoethyl) (2-methoxy-2-oxoefhyl)-4-cyano-3-(2-
ethoxy-2- oxoethyl) thiophen -2-carboxylate.
XXI. Methyl 5-(bis (2-amino-2-oxoethyl) amino)-4-cyano-3-(2-methoxy-2-
oxoethyl) thiophene-2-carboxylate.
XXII. Ethyl 2-(5-((2-amino-2-oxoethyl) (2-methoxy-2-oxoethyl) amino)-2-carbamoyl-4-cyanothiophen-3-yl) acetate.
XXIII. Ethyl 3-(2-amino-2-oxoethyl)-5-(bis (2-methoxy-2-oxoethyl) amino)-4-cyanothiophene-2-carboxylate.
XXIV. Ethyl 5-(bis (2-amino-2-oxoethyl) amino)-4-cyano-3-(2-methoxy-2-oxoethyl) thiophene-2-carboxylate.

7. The process according to claim no. 1 wherein reaction of a compound of formula V with strontium hydroxide is carried out in organic solvent or water.
8. The process according to claim no. 7, wherein organic solvent is selected from the group comprising of alcohols such as methanol, ethanol, propanol, isopropanol. n-butanol or isobutanol; ethers such as tetrahydrofuran or dioxane; ketones such as acetone, methyl ethyl ketone, methyl butyl ketone, methyl isobutyl ketone, dipropyl ketone diisopropyl ketone, diethyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl propyl ketone or ethyl isopropyl ketone.

9. The process according to claim no. 2 wherein the reaction of a compound of
formula VI with ammonia is carried out in the presence of ammonium sulfate.
10. The process according to claim no. 4 wherein reaction of a compound of formula
VII with 2-bromoalkylamide is carried out in the presence of inorganic base such as
sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
sodium hydride or sodium methoxide in an alcoholic solvents such as methanol,
ethanol n-propanol, isopropanol. n-butanol, isobutanol, n-pentanol or isopentanol.