Title of Invention	AN IMPROVED PROCESS OF PREPARING AMPICILLIN TRIHYDRATE
Abstract	An inproved process for the preparation of ampicillin trihydrate via Danes salt, from D(-)-phyenyl glycine and potassium salts Via potassium hydrate like carbonate etc, followed by treatment with ethyl or methyl acetoacetate and thereafter to yield ampicillin.

Full Text

FORM 2 intermediate leading to a sizeable and significant reduction in the manufacturing cost of the final target molecule ampicillin. Description: - According to the present invention relates to an improved process for the preparation of ampicillin trihydrate via Danes salt , from D(-) -phenyl glycine and potassium salts Via potassium hydrate like carbonate .etc, followed by treatment with ethyl or methyl acetoacetate and thereafter to yield ampicillin comprising the following steps, A) Preparation of mixed an hydrate B) Preparation of 6 amino pencillanic acid (6 APA) C) Preparation of quaternary salt of 6 APA D) Preparation of ampicillin trihydrate , wherein reacting D(-)- phenyl glycine with potassium salts with or without requisite quantity of water , using various ketonic solvents , such as MEK ( methyl ethyl ketone ) acetone , MIBK (i*«-tty. iVivd^l ) in particular at temperature ranging from below ambient to 90 C , in particular from 40 C to 80C , followed by the azeotropic removal of the water if required and finally reacting this mixed an hydrate or suspension with ethyl or methyl acetoacetate to obtain the desired Dane"s salt and from which proceeding by the technique to prepare ampicillin , Detail description: - An improved process of the present invention for manufacturing ampicillin trihydrate from D-o£- phenyl glycine base comprising the following steps wherein, taken a D- 06- phenyl glycine base into a dry and clean flask, and charged with methyl ethyl ketone and added potassium salt of potassium carbonate using base such as water formed potassium salt of base, to this added ethyl acetoacetate at room temperature, the above reaction mass was allowed to heat at 40 C to 90C more particularly heating temperature maintained at 83C to 85C for a period of 40 to 50 minute , followed by azeotropic distillation using slow vacuum at 70C to 75C to remove water completely from the reaction mixture further above reaction mass allowed to degas a reaction mass completely until to become free from methyl ethyl ketone , after degassing reaction mass is allowed to cool at 35C to 40C and charged with methylene chloride followed stirring until to get clear solution , chilled the reaction mass below - 45C and charged with liquid catalyst -1 , such as pyridine under constant checking of the moisture limited to 0.5% and further added (PVC) polyvinyl chloride at - 45C and maintained the reaction temperature at -33C to -37C , for a period of 30 minutes and the reaction mass again maintained the temperature at -43C to -47C for a period of 30 minutes , after 30 minute s allowed to chill at -53 C then after added a catalyst B-2 , again kept reaction mass at -53C to 57C for a period 30 minutes to form a mixed an hydrate stage of Danes salt , to this salt added try ethyl amide complex to the reaction mass followed by condensation at -55C to -50C for 2 hours further maintained the reaction mass at -50C to -45C for two hours , to this mass reaction charged with iso propyl alcohol , pure water and hydrochloric acid , stirred for a period of 7 minutes until to settle the reaction mass , separates the methylene chloride layer ,using extraction process in which 44 ml, of pure water and 2 ml of H61 , added aqueous layer to the main reaction mass to measure the methylene chloride crude quantity . Chilled the aq. Layer at 0C to 2C , added aq. Ammonia slowly to the reaction mass adjusting the PH between 5 to 5.2 with an hour and also stabilise the precipitated mass at 0 to 2C wash the precipitated mass with chilled water , repeated with iso propyl alcohol and with water mix ( ratio &° i_2£& resultant mass allowed to dry at 50 to 55 C Preparation of Try ethyl amide complex, Charged methylene chloride 190 ml and added 6 APA (amino penicilloic acid) 100 gr at room temperature allowed to chill at 0 to 5 C and added try ethyl amide (54 gr) to the above reaction mass, and added water 19 ml, at 5 to 10C following by constant stirring for a period of 45 minutes charged with iso propyl alcohol at 5 to 10 C again chilled to 0 to 2 C resultant try ethyl amide shall be transferred to the reaction mass. Example 1, Preparation of D (p0 phenyl glycine ethyl potassium Dane salt from base by using acetone as ketonic solvent, An acetone 300 ml charged to a clean and dry flask and added 23 gr, of potassium carbonate and any base 50 gr, and 10 ml of water, 44 gr of ethyl aceto acetate is added to the above reactants and allowed to reflux under heating at 32 C to 75C for 3 hours . After completion of the reaction acetone was distilled out following a degassing by applying vacuum at 57C to 60C for a period of 35 minute. After degassing charged 400 ml of iso propyl alcohol again allowed to reflux for a period of 35 minutes at 50C to 81.2C. The above reaction mass allowed to cool and chill at 0 to 2 C for a period of 35 minutes, resultant reaction mass filtered and flushed with iso propyl alcohol and above white crystalline product obtained having following properties Wet wt; 140 gr, and product contains the moisture 1.16% dry wt 92.5 gr, moisture .5% assay 99.2% Ph 9.5. SOR-79.91 yield 1.852 Note. Used iso .propyl alcohol only for the purpose of isolation Danes salt. The reaction taken place in acetone reaction can be taken forwarded to ampicillin after degassing of acetone. Example 2. Preparation D (^) phenyl glycine ethyl potassium Dane salt from base using MEK , methyl ethyl ketone , charged 150 ml of methyl ethyl ketone , 23 gr of potassium carbonate 50 gr of base , and 10 ml water and 44 gr, of ethyl aceto acetate to a clean and dry flask allowed to heat and reflux at 32 C to 75.4C for a period of 60 minutes and distilled out the solvent using distillation process at 75C 95C for a period of 35 minutes and followed by vacuum degassing at temperature 95C to 72C for a period of 15 minutes . Then charged an iso propyl alcohol 400 ml followed by heating at 56C to 82C for a period of 30 minutes .the resultant reaction mass allowed to cool and chill to 0 to 2C for a period of 55 minutes. Filtered and flushed with iso propyl alcohol 100 at 0C for a period of 15 minutes. Note , Used IPA only for the purpose of isolation of Dane salt > reaction taken place in methyl ethyl ketone ( MEK ) reaction can be taken forward to ampicillin after degassing of MEK . We claim, 1. An improved process for the preparation of ampicillin teg hydrate from D - - phenyl glycine base comprising the following steps > a) Reacting D - oC - phenyl glycine base with a potassium salt using solvent and with ethyl aceto acetate at a temperature range from 40C to 90C for a period of 40 minutes b) Azeotropic distillation of reaction mass obtained at step (a) using slow vacuum c) Degassing the reaction mass obtained at step (b) d) Cooling the reaction mass of step ( c ) and charged with methylene chloride followed by stirring until to get clear solution e) Chilled the reaction mass obtained at step ( d ) and charged with liquid catalyst - 1 , under constant checking of moisture and added polyvinyl chloride and maintained the reaction temperature from the range of-33 to -50C followed by further chilling at -53C then added catalyst B-2 at a temperature range from -50 C to -57C for a period of over 30 minutes to give a Danes salt, t f) Added try ethyl amide complex to the above followed by condensation , and further added iso propyl alcohol, water and H61 followed by stirring until to get settled the reaction mass, g) Extraction of organic layer using water and hydrochloride h) Chilled aq.layer and followed by adding ammonia to adjust JS,©^ i) Filtered followed by washing and dry, 2. A process as claimed in claim 1, wherein the solvent used selected from methyl ethyl ketone, ketonic solvent, 3. A process as claimed in claim 1 and 2, wherein the heating temperature was maintained from 83C to 85C, 4. A process as claimed in claim 1 to 3 wherein the temperature 83C to 85C is maintained over a period of 40 minutes, 5. A process as,claimed in claim 1, wherein an azeotropic distillation is carried out using slow vaccum at a temperature range from 70C to 75C, until to remove water completely, 6. A process as claimed in claim ^and 5, wherein the reaction mass allowed to degassing until to become free from methyl ethyl ketone, 7. A process as claimed in claim land 6, wherein the reaction mass is allowed to cool at 35C to 40C, 8. A process as claimed in proceeding claims wherein the methylene chloride is charged followed by stirring, 9. A process as claimed in claim 8, wherein reaction mass allowed to chilled below -45C 10. A process as claimed in claim 1, wherein the liquid catalyst used such as pyridine, 11. A process as claimed in claim 1 and 10, wherein the moisture limit maintained to 0.5% 12. . A process as claimed in claim 11, wherein the reaction temperature maintained at -3 3 C to -3 7C 13. A process as claimed in claim 1, wherein the wherein-the catalyst -B-2 used selected &©*H~#iey*Jro-ro. 14. An improved process for the preparation of ampicillin trjf hydrate from D -OC - phenyl glycine base such as here in described with reference to forgoing examples and description. Dated this 6TH day of June 2004

Documents:

709-mum-2004-abstract(05-07-2004).doc

709-mum-2004-abstract(05-07-2004).pdf

709-mum-2004-cancelled pages(05-07-2004).pdf

709-mum-2004-claims(granted)-(05-07-2004).doc

709-mum-2004-claims(granted)-(05-07-2004).pdf

709-mum-2004-correspondence(27-08-2004).pdf

709-mum-2004-correspondence(ipo)-(06-10-2004).pdf

709-mum-2004-form 1(05-07-2004).pdf

709-mum-2004-form 19(05-07-2004).pdf

709-mum-2004-form 2(granted)-(05-07-2004).doc

709-mum-2004-form 2(granted)-(05-07-2004).pdf

709-mum-2004-form 3(05-07-2004).pdf

709-mum-2004-form 5(05-07-2004).pdf