Technical field of invention
The present invention relates to large scale process for the production of 5'-(S)-l,5- . dioxo-(5'-ethyl-5'-hydroxy-2'H,5H,6'H-6-oxopyrano)-[3',4',f]-∆ 6,(8)-tetrahydro
indolizine, referred as (S)-Trione (14) a useful intermediate for the preparation of camptothecin analogs in high yield and purity. The present invention also discloses the conversion of the undesired (R)-Isomer (15) to the racemic product (11), which is then recycled to obtain required (S)-Trione (14).

Background and prior art
Camptothecin is a pentacyclic alkaloid, first isolated from the wood and bark of camptotheca acuminate by Wall et. al.[JACS, 94, 388 (1966)]. It exhibits potent antitumor activity.

Camptothecin represented by the following formula;
has been known to have the S-configuration at the 20 position. It has therefore been desired to provide synthetic intermediates which permit advantageous preparation of camptothecin having the S-configuration and its derivatives.

Several methods for the synthesis of camptothecin and camptothecin analogs are knovm. Natural camptothecin is synthetically converted to either Irinotecan or Topotecan, the two drugs which are widely used in medicine. This semi-synthetic approach has been reported
in US patent Nos. 4,604,463; 4,545,880 and 4,473,692, European patent application no.EP0074256 as well as in Japanese patent Nos. JP84/46,284 and JP84/51,287.

However, the commercial production of Irinotecan and Topotecan synthesized from natural camptothecin, is laborious to obtain in pure form.

Camptothecin synthesis was first reported by Wani et.al. [J.Med.Chem. 554 (1980)] by adopting Friedlander synthesis and the same was extended by Tagawa et.al.

US patent no. 4,778,891 (1988) discloses synthesis of 7-ethyl-lO-hydroxycamptothecin (SN-38) from which Irinotecan is made. SN-38 is made by condensing 2-Amino-5- hydroxypropiophenone (AHPP) with (S)-Trione (14) in accordance with the following reaction scheme (Figure 1). Earlier AHPP was synthesized according to the synthesis disclosed in PCT/IN2005/000326, WO 2007/015259 and (S)-Trione by adopting the method reported by Wani et.al (J.Med.Chem. 554,1980 and 1553,1986)

Preparation of (4S)-4-Alkyl-7,8-dihydro-4-hydroxy-1 H-pyrano[3,4-f] indolizine-3,6,10- (4H)-trione Compound (10), is disclosed in J. Med.Chem., 554(1980) as per the scheme mentioned below. In the reaction scheme, the reaction for obtaining 6-cyano-l,l- (ethylenedioxy)-7-[(alkoxycarbonyl)-alkyl]-5- oxo-A6(8)-tetrahydroindolizine (7) from Compound (1). Further the enol etheri fication step disclosed in the said process is effected in presence of ammonium chloride as a catalyst which takes seven days to complete. Further the cyclisation of compound (3) from compound (2) and of compound (4) from compound (3) in presence of solvent requires longer reaction hours to complete the reaction. Also,the ketalization reaction of compound (5) which takes place in the presence of p-toluenesulfonic acid as a catalyst requires large amount of solvent and longer reaction hours, thus making the reaction cumbersome.

Subsequently, US6337400 discloses an improved method over the method disclosed in J. Med.Chem., 554(1980), for preparation of 6-cyano -1,1 [ethylenedioxy]-[(ethoxycarbonyl)-l-methyl]-5-0X0 tetrahydro indoziline (7) from alkylacetopyruvate(l).
Thus the methods reported in prior arts including the process disclosed in Wani et.al (J.Med.Chem. 1980, 554) are met with several problems such as prolonged reaction time, inferior operability and use of dangerous reagents and not amicable for large scale production. Further large quantities of solvents are used at many stages, besides several reactions that are not conducive for large scale operations. Hence there was need to improve the method reported by Wani et.al (J.Med.Chem. 1980, 554) and to develop a superior process that can be operated on large scale. This remains the object of the present invention.

Summary of the invention
In line with the objective, several improvements have been made after extensive investigations resulting in a simplified process for the large scale production of (S)- Trione.

In one aspect, the present invention involves the preparation of compound (1) by reacting acetone with ethyl oxalate in presence of commercial sodium methoxide (made from NaOH and methanol). The mixture (la & lb) is then converted to the enol ether (2) by reacting with ethyl orthoformate in absolute ethanol using a strong acid as catalyst.
The enol ether (mixture of 2a & 2b) is then converted to compound (3a and 3b), by reacting with cyanoacetamide in acetone in presence of base such as potassium carbonate to accomplish reaction faster. Compound (3a and 3b) are further reacted with methyl acrylate in DMSO in presence of 2,6-di-tert-butyl-4-methylphenol and potassium carbonate. The reaction takes 6 to 12 hrs for completion and throwing out the potassium salt (4a). It is preferred to collect the potassitum salt (4a) from DMSO whereby most of the DMSO can be recovered and reused in the subsequent operations. The potassium salt is then suspended in water and acidified with HCl to obtain compound (4b) and then decarboxylated to obtain 6-Cyano-7-methyl-l,5-dioxo-A-∆6,(8) -tetrahydroindolizine (5).

Decarboxylation of (4b) is carried out as per the known art and converted the compound (5) toits ketal derivative by heating with a mixture of ethylene glycol and trimethylsilyl chloride in methylene chloride to obtain compound (6). Compound (6) is then converted to compound (7) by reacting with diethyl carbonate in presence of a mixture of sodium hydride and potassium tert-butoxide (3:1) in tetrahydrofuran.

The alkylation of compound (7) to compound (8) is carried out using ethyl iodide and a suitable base in prior art methods. However, there are several disadvantages in using ethyl iodide such as cost, toxicity and invariable contamination with traces of Mel, resulting in the formation of the corresponding 5'methyl analog of the (S)-Trione. Such problems have not been encountered with the use of ethyl bromide. Accordingly, the alkylation of compound (7) to compound (8) is carried out with ethyl bromide (2 eq.) in
THF for 24 hrs at room temperature and preferably using a phase transfer catalyst such as tetraalkylammonium iodide to drive the reaction to completion.

Compovmd (8) is then converted to the racemic dione (11) which is then resolved to the desired (S)-Isomer (12a) by using (S)-a-methylbenzyl amine. Lactonisation of (12a) in acetic acid yields compound (13) which is smoothly converted to the final (S)-Trione (14) by heating with formic acid at 60-65°C for 3 hrs. The (S)-Trione (14) thus obtained is more than 99.6% pure by HPLC with the traces of (R)-Isomer is less than 0.1%.

In another aspect, the unwanted (R,S)-amide (12b) is converted to the predominant (R)- Isomer (15) which is further converted to the desired (S)-trione (14) by the sequence of reactions depicted in scheme 9, which forms another part of the invention.

Thus the present inventors have achieved a better method of manufacturing (S)-Trione, the key intermediate required for the synthesis of SN-38 leading to Irinotecan.

DETAILED DESCRIPTION OF THE INVENTION

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Accordingly, the present inventors conducted extensive investigations at every stage and finally arrived at a commercially feasible route for the production of (S)-Trione (14) under improved conditions and operations that are easy to perform on industrial scale.
According to the preferred embodiment, the process for the preparation of (S)-trione depicted in the following Schemes:

Scheme 1:
Preparation of ethyl/methyl acetopyruvate (1) which involves condensation of acetone with diethyl oxalate in presence of sodium methoxide (made from NaOH and methanol) in methanol, avoiding sodium ethoxide which is made by dissolving sodium metal in
absolute ethanol. Compound (1), thus obtained is a mixture of methyl and ethyl esters (la and lb) wherein the methyl ester formed due to trans esterification is more than 90%;..

Scheme 2:
Converting the mixture (la and lb) to Ethyl / Methyl (2-ethoxy-4-oxo) pent-2-enoate (2) which involves reacting the mixture with ethyl orthoformate (1 to 1.5 eq.) in absolute ethanol using catalytic quantity of organic acid such as dodecylbenzenesulphonic acid, p- toluenesulphonic acid etc. (0.01 to 0.1 eq.) and refluxing for 1 to 2 hrs at 50-60°C. Compound (2) obtained is also a mixture of (2a) and (2b) wherein ethyl ester is formed to the extent of 60 to 70% due to trans -esterification with excess of ethanol;

Scheme 3:
Converting compound (2) to compound (4) either by isolating compound (3) or without isolating compound (3)

Accordingly, compound (2) is heated with 2-cyanoacetamide (1 to 1.5 eq.) in a suitable polar solvent such as alcohols, dialkyl ketones, DMF, DMSO etc. and in a base (1.5 eq) selected from organic or inorganic bases such as metal alkoxides like sodium methoxide sodium ethoxide and the like; alkali metal carbonates like sodium or potassium carbonate and the like; preferably either potassium carbonate or sodium methoxide. The reaction is preferably carried using acetone or methanol as solvent by refluxing the medium for 6 to 8 hrs. The compound thus obtained is also a mixture of methyl and ethyl ester (3a and 3b) in the same ratio as in compound (2)

Further, compound (3) is converted to compound (4) by taking compound (3) in DMSO (10 times), adding methyl acrylate (3 eq.) and potassium carbonate (1.5 eq.) followed by addition of radical inhibitor such as 2,6-di-/er/-butyl-4-methyl phenol (BHT 0.1 eq.) etc. [The use of BHT makes it possible to reduce the quantity of methyl acrylate( from 8.0 to 3.0 eq.) to complete the reaction, thereby inhibiting polymerization. Also, the use of less quantity of methyl acrylate makes this operation cost-effective and safer.]

The above reaction is performed by heating the reactants for 6 to 12 hrs at 60-80°C. On cooling, the reddish potassium salt (4a) is precipitated out. The present inventors have observed that instead of diluting the medium with large quantities of water and further acidifying to obtain compound (4b), it is advantageous instead to collect the potassium salt (4a) by centrifuging the solution. After the isolation of compound (4a), the solvent could be distilled and reused in the next operation. Alternately, the potassium salt (4a) is filtered, suspended in water, acidified with conc. HCl or H2S04 to obtain pale yellow solid (4b) with purity >95% by HPLC.

Alternately, compound (2) is converted to compound (4a) in one pot by first reacting enol ether (2) with 2-Cyanoacetamide in DMSO, using potassium carbonate as the base and heated to 70°C for Ihr. To this hot solution methyl acrylate (3.0 eq.) and 4,6-di-tert- butyl-4-methylphenol (0.1 eq.) is added and continued heating for further 6 to 12 hrs to complete the conversion of (3) to (4a) and isolating the resulting potassium salt (4a) by filtration.

The above one pot reaction can be carried out using other acrylate esters such as n-butyl acrylate or tert-butyl acrylate, the latter offers some advantages in handling the operations. Same quantity (3 to 5.0 eq.) of tert-butyl acrylate is used in presence of a radical inhibitor such as BHT, heating to 70°C for 6 hrs to complete the conversion of compound (3) to compound (4). In a similar manner the salt is filtered, suspended in water and acidified to pH 2 to give the tert-butyl ester.

The conversion of compound (2) to (4) via (3) in situ by the earlier workers was found to be cumbersome and involved in handling excess of methyl acrylate (8 to 20 eq.). Further, higher volume of solvent and subsequent dilution with water (10 times) was observed to be not practicable to perform this operation on large scale.

Scheme 4:
Compound (4b) is decarboxylated by heating it to 80-100°C in a mixture of acetic acid and conc. HCl (10 times each) for 4 to 6 hrs. The acid solution is then distilled; followed by addition of water to obtain compound (5).

This is followed by Ketalization of compound (5) to compound (6) with ethylene glycol in presence of lewis acid or more preferably by using trimethylsilyl chloride (10 eq.) in a chlorinated organic solvent such as methylene chloride and heating to 50°C for 24 hrs. The reaction also proceeds equally well in a shorter time in acetonitrile and heating to 50°C in presence of trimethylsilyl chloride (3 to 5 eq.) for 12 to 24 hrs.

Scheme 5:
This step involves carbonylating compound (6) to obtain compound (7) with diethyl carbonate in presence of a mixture of sodium hydride and potassium rerr-butoxide in the ratio (3:1 eq.) in a solvent such as THF at 45-50°C temperature for 10 hrs. Earlier Wani et.al (J.Med.Chem. 1980, 554) employed potassium hydride for carbonylation of compound (6) to obtain compound (7). Others have used sodium ethoxide, potassium /er/-butoxide etc. in CH2CI2 or DME and heating with diethyl carbonate to 90-100°C.

The present inventors found that it is too risky to use potassium hydride as the base. It is observed however that a mixture of sodium hydride and potassium /er/-butoxide in the ratio (3:1 eq.) gave the best results in carbonylating compound (6) in tetrahydrofuran at 45-50°C temperature for 10 hrs. The conversion is almost quantitative and the compound can be carried out to the next operation without any further purification.

Scheme 6:
Compound (7) is alkylated to obtain compound (8) and is advantageously carried out with ethyl bromide in presence of a phase transfer catalyst such tetraalkylammonium iodide, TBAB etc preferably, tetraalkylammonium iodide in THF in presence of potassium /er/-butoxide at room temperature for 15 to 24 hrs.

Further, ethyl bromide (1.5 to 2 eq.) and PTC (0.05 to 0.2 eq.) are critical for the reaction to proceed in any polar medium. THF (10 to 15 times) is the most suitable solvent for the operation purpose and can be recovered. The compound (8) obtained is >95% pure by HPLC.

In the known art, alkylation of compound (7) to compound (8) is carried out using ethyl iodide and a suitable base. There are several disadvantages in using ethyl iodide such as cost, toxicity and invariably contaminated with traces of Mel, resulting in the formation of the corresponding 5'methyl analog of the (S)-Trione. However such problems have not been encountered with the use of ethyl bromide.

Scheme 7:
Compound (8) is then hydrogenated to acetamido derivative (9) which is further reacted with sodium nitrite at low temperature to give intermediate (10) followed by bubbling oxygen through the solution of compound (10) to yield compound (11).

Accordingly, compoimd (8) is hydrogenated in acetic acid and acetic anhydride medium at 80-100 psi in presence of a suitable catalyst such as palladium/carbon, Raney Nickel, platinum etc, preferably Raney Nickel. The acetamido derivative (9), thus obtained in acetic acid and acetic anhydride medium is filtered to remove the catalyst from the medium and this filtrate is then cooled to 0-5 °C followed by addition of sodium nitrite (2 to 4 eq.) and allowed to stir for 10 to 12 hrs at room temperature. After the reaction, the medium is heated to 80°C to distill out most of the acetic acid and acetic anhydride left in the reactor. The contents were dissolved in toluene, heated the organic phase to 60-80°C to dissolve the compound, cooled and washed with water. Toluene is then distilled out to obtain compound (10), which is then taken in methanol to which potassium carbonate (1 to 2 eq.) is added and bubbled oxygen through the solution where more than 80% conversion of compound (10) to compound (11) is achieved. The solution is cooled, acidified and distilled the solvent to give compound (11). From the mother liquor unreacted compound (10) is further extracted with CH2CI2 and converted to (11) by bubbling oxygen as indicated above to yield additional quantity.

Scheme 8:
The racemic compound (11) is reacted with (S)-a-methylbenzyl amine to pure (S,S)- amide (12a) followed by lactonisation in presence of acid and deketalization to yield the desired S-trione(14) with purity >99.6%.

Thus to the racemic compound (11) is added (S)-a-methylbenzyl amine (2 to 4 times), and heated to 90°C for 3 to 4 days in nitrogen atmosphere. The excess of (S)- a-methylbenzyl amine is removed under reduced pressure, the residue is stirred with toluene, cooled to 0-5°C and left for 12 hrs to give pure (S,S)-amide (12a) which is 99.8% pure by HPLC with unwanted (R,S) diastereomer (12b) less thenO.1%. The compound (12a) is then lactonised to compound (13a) by heating with acetic acid.

Finally, deketalization of compound (13a) is carried out by heating with any acid in an organic solvent medium to obtain S-Trione (14). Accordingly, compound (13a) is heated in formic acid at 60-65°C for 2 to 3 hrs and then crystallized from ethyl acetate to obtain S-Trione (14) having 99.8% chiral purity which was further converted to SN-38 with purity >99.6%.

Earlier, the unwanted (R)-Isomer (15) was converted to the desired (S)-Isomer (14) and also carried over to the racemic compound (11). However, the present inventors found these methods, are not suitable to large scale conversion.

Therefore, in another embodiment (Scheme 9), the unwanted (R,S)-amide (12b) is subjected to acid hydrolysis, preferably by refluxing with acetic acid to give (R)-Isomer (15) having 5 to 10% of the (S)-Isomer (13a). This compound is then converted to its chloro derivative (16) by heating with phosphorus oxychloride in presence of an organic base such as pyridine, triethyl amine, 4-dimethylaminopyridine etc. The chloro compound (16) is then converted to compound (17) by hydrogenolysis using 5% Pd/C at 50 Psi. The compound (17) is then smoothly taken to the racemic product (11), which is then recycled by the same sequence of reactions to give the desired (S)-Trione.

Thus the present invention demonstrates a simple and feasible approach for the synthesis of (S)-Trione (14) on a large scale with high purity.

The examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples;
Example 1: Ethyl / Methyl acetopyruvate (1)
To a 1000 L S.S. reactor, was added solid sodium methoxide (56 kg) and methanol (560 L) and stirred for 1 hr and brought the internal temperature below 10°C. A mixture of diethyl oxalate (100 kg) and acetone (56 L) was added from an additional tank over a period of 2 hrs; keeping the internal temperature below room temperature. The contents were stirred for an additional 12 hrs at room temperature. At the end of the reaction, sodium salt of the resulting pyruvate (1) was thrown out. The solid was collected. It was then added slowly with stirring to dilute sulphuric acid in a glass lined reactor (300 L of H20,46 kg of sulphuric acid), keeping the temperature below 30°C. After stirring for 30 minutes, the compound was extracted into methylene chloride (300 + 100 L). The organic layer was collected, solvent was removed and the mixture of methyl and ethyl acetopyruvate was collected (72 to 75 kg)

Example 2: Ethyl / Methyl (2-ethoxy-4-oxo) peiit-2-enoate (2)
The acetopyruvate (1) so obtained (72 kg) was added to a mixture of absolute ethanol (210 L) and ethyl orthoformate (135 kg), taken in a glass lined reactor. To this 4- dodecylbenzenesulphonic acid (1.5 kg) was added and the mixture was heated to 40°C for 2 hrs. pH of the solution was adjusted with aqueous NaOH solution to neutral and the solvent was removed to give compound (2) (75 to 78 kg). It was distilled under reduced pressure. The compound is a mixture of (2a) and (2b), the ethyl ester being predominant.
Example 3: Ethyl / Methylcarbonyl-3-cyano-4-methyl-2-pyridoiie (3)
To a stirred solution of above compound (2) (17.4 kg) in acetone (175.0 L) in S.S.

Reactor, potassium carbonate (20.7 kg) and 2-cyanoacetamide (9.24 kg) were added and the contents were heated to 65-70°C for 6 hrs. The red slurry was filtered, suspended in water (100 L) and acidified with conc. HCl till the pH of the solution was 1.5. The compound was collected and dried (15.6 kg). The product is a mixture of methyl and ethyl esters (3a & 3b). The compound is >95% pure by HPLC analysis.

Example 4: 2-(Ethyl/Methylcarboxy)-6-Cyano-7-methyl-l,5-dioxo- A®'^®^-tetrahydro indolizine (4b)

To a stirred solution of above compound (3) (15.0 kg) in DMSO (150.0 L), potassium carbonate (19.2 kg), methyl acrylate (25.8 kg) and 2,6-di-rerr-butyl-4-methylphenol (0.2 kg) were added and heated the contents to 40°C for 10 to 12 hrs. The resultant potassium salt (4a) was thrown as dark brown solid. This was collected by filtration. The salt (4a) was suspended in water (200 L) and conc.HCl was added under stirring till pH 1.5. The ester (4b) was collected by filtration, washed with water and dried (16.35 kg)
Example 5: 6-Cyano-7-methyl-1.5-dioxo- A -tetrahydroindolizine (5)

The compound (4b) obtained above (16.35 kg) was suspended in a mixture of conc.HCl (160.0L) and acetic acid (160.0 L) and heated the contents to 6 hrs at 90-100°C. After that, the acid solution was recovered under reduced pressure, water was added, cooled and collected compound (5) (8.6 kg)

Example 6: 6-Cyano 7-Methyl-l,5-dioxo-A-∆ 6,(8)-tetrahydroindolizine (5)
The above enol ether (2) (35.0 kg) was added slowly to a stirred mixture of potassium carbonate (41.4 kg), cyanoacetamide (16.8 kg) in DMSO (350 L) and heated the contents to 70°C for 2 hrs. To this hot solution under stirring, methyl acrylate (51.6 kg: 3.0 eq.) and 2,6-di-tert-butyl-4-methylphenol (0.4 kg) were added and the reaction medium heated to 70°C for further 12 hrs. The red slurry containing the potassium salt (4a) was collected. The wet salt was then suspended in aq.HCl (25.0 L HCl in 250.0 L H2O) and stirred for 2 hrs and collected the wet cake.

The above wet cake (4b) was taken in a mixture of conc.HCl (250 L) and acetic acid (250 L) and heated the contents to 90-100°C for 6 hrs. The acetic acid solution was distilled under reduced pressure, cooled the contents, water (150.0L) was added, stirred for 2 hrs and collected the product (16 kg). The dark brownish compound is >95% pure by HPLC.
Example7:6-Cyano-l,l-[ethylenedioxy]-7-methyl-5-oxo-A-∆ 6,(8)-tetrahydroindolizine(6)
The above compound (5) (4.18 kg) in CH2CI2 (836 L) was treated with ethylene glycol (3.04 kg; 2.2 eq.) and to this trimethyl silylchloride (10.74 kg; 4.4 eq.) was added slowly and stirred at room temperature for 24 hrs. The organic layer was washed with 1 M
aqueous NaOH sol. (60.0 L) and then with water. It was filtered through celite bed and the solvent was removed to afford ethylene ketal (6) (3.1 kg) as brownish solid.

Example 8: 6-Cyano-l,l-[ethylenedioxyl-7-[(ethoxycarbonyl)-l-methyll-5-oxo-A tetrahydroindolizine (7)

The compound (6) (2.32 kg) obtained above was taken in THF (25.0 L) and to this sodium hydride (0.72 kg) and Potassiumtert-butoxide (1.126 kg; 1.0 eq.) were added. To this solution diethyl carbonate (3.72 kg, 4.0 eq.) followed by catalytic quantity of absolute ethanol (0.2 L) were slowly added and heated gradually to 50-55°C and maintained the temperature for additional 10 hrs. (the process check showed the starting material less than 5%). The contents were cooled to 0-5°C and acetic acid (3.0 L) was added slowly followed by water (75 L). The blackish solid was collected and dried to give compound (8) (2.25 kg).

Example 9: 6-Cyano-1,1 -ethylenedioxy-7- [1' -(ethoxycarbonyl)-propy 1] -5-oxo- tetrahydroindolizine (8)

To a stirred solution of the above ester (7) (3.0 kg) in tetrahydrofuran (45.0 L), potassium rer/-butoxide (1.23 kg, 1.1 eq.) was added and stirred for 30 minutes at room temperature.
Ethyl bromide (2.18 kg; 2 eq.), tetrabutylammonium iodide (0.74 kg; 0.2 eq.) were added
and stirred at room temperature for 24 hrs. (the process check shows the reaction is completed and the starting material is <1%). The reaction was then quenched by adding water (14 L) slowly. Tetrahydrofuran was removed by distillation, water (700 L) was added, stirred and filtered the compound. Grey colored compound was dried to give compound (8) (2.91 kg) with purity >95% by HPLC.

Example 10: (6-Acetoxymethyl)-l,l-(ethylenedioxy)-7-[(r-ethoxycarbonyl) propyl]- 5-0X0- A-tetrahydroindolizine (10)

The above solution of compound (8) (2.62 kg) in acetic anhydride (21.2 kg) and acetic acid (6.86 kg) was hydrogenated in presence of Raney Nickel (1.57 kg) at a pressure of 100 psi and keeping the temperature 50°C for 8 hrs. The solution was filtered to remove the catalyst. To the filtrate, maintaining the temperature at 0-5°C, sodium nitrite (1.83 kg, 3.33 eq.) was added and stirred at room temperature for 12 hrs. Any undissolved inorganic salts were removed by filtration and acetic anhydride and acetic acid were removed under reduced pressure. To the oil, toluene (28.0 L) was added, stirred well with heating at 75°C for 6 hrs, cooled to room temperature and washed the toluene layer with water (3 x 18 L) thrice and the toluene was removed to give compound (10) (3.8 kg).
Example 11: l,l'-Ethylenedioxy-5-oxo (5'-ethyl-5'-hydroxy-2'H,5'H,6'H-6- oxopyrano)-[3',4'-]-∆ 6,(8)-tetrahydro-indolizine (11)

Compound (10) (3.8 kg) was dissolved in methanol (45.0 L) and to this anhydrous potassium carbonate (1.3 kg; 1.2 eq.) and oxygen was bubbled through the mixture for 2 hrs. At this stage 80% of the compound (10) was oxygenated to compound (11) by HPLC analysis. The solution was transferred into a glass lined reactor, cooled to 10- 20°C and slowly acidified with IN H2SO4 (15.0 L) to pH 6. Distill methanol under reduced pressure below 50°C temperature. Cooled to 20°C and added water (10.0 L) and adjust the pH to 3. The aqueous solution was extracted with methylene chloride twice (40 and 10 L). The solvent layer was washed with water (10.0 L) and methylene chloride was removed by distillation. The solid was stirred with acetonitrile (1.0 L), filtered to give compound (11) (1.52 kg)

Example 12: Resolution of l,r-Ethylenedioxy-5-oxo (5'-ethyl-5'-hydroxy- 2'H,5'H,6'H-6-oxopyrano)-[3',4'-fi- A'''<'')-tetrahydro-indolizine (11) to amide (12a) Compound (11) (5 kg) is suspended in (S)-a-methylbenzylamine (15 L) and heated to 90- 100°C for 3 days. (At the end the process check shows the absence of the starting material). The excess (S)-a-methylbenzylamine was removed by distillation under reduced pressure, keeping the bath temperature below 110°C. The residue (7.1 L) was cooled to 0-5 °C and diluted with toluene (20 L) under stirring. The solution was kept at 0-5°C for 12 hrs and the pure (S,S)-amide (12a) was collected by filtration and air dried. The optical purity of (S,S)-amide (2,3 kg) by HPLC shows 99.9% and the other diastreomer, (R,S) amide (12b) is <0.1%. [a]D-54°C(conc.CHCl3 / MeOH 4:1)
Example 13: S-Dione Compound (13)

The above amide (12a) (2.3 kg) was taken in acetic acid (4.6L) and heated to 65-70°C for 3 hrs. Distill part of the acetic acid up to 60% using reduced pressure. The syrupy dark colored compound was taken in methylene chloride (20 L) and washed with sat.solution of potassium carbonate (pH 6.8) and the solvent was filtered. The solvent was removed to obtain foam like product. It was dissolved in ethyl acetate, stirred at room temperature and filtered the product (13) (1.25 kg). Purity 99.7% HPLC [a]D+ 85, R-Isomer <0.1%.
Example 14: Preparation of (S)-Trione (14)

Compound (13a) (1.25 kg) was taken in formic acid (3.75 L) and heated to 60-65°C for 3 hrs. Formic acid was removed to the extent possible (35 to 40%) and ethyl acetate (1.25 L) was added and heated the contents 65-70°C. The clear solution was then cooled to 0- 5°C and the solid was collected, washed with hexane (3.0 L) to remove the adhering HCO2H. The colorless compound (14) (0.8 kg) was collected and air dried. [a]D+108 Chiral purity 99.9%.

Example IS: Conversion of (R,S)-amide (12b) to R-Isomer (15)
The toluene solution after removing (S,S)-amide (12a) contained predominantly (R,S)- amide (12b) together with (S,S)-amide (8-10%). Toluene (40 L) was taken together into a reactor and the solvent was removed to give a syrupy compound (11.2 kg). It was then stirred with n-hexane (40 L) at room temperature to remove the excess of (S)-a- methylbenzylamine. The insoluble viscous mass (6 kg) was subjected to alkaline hydrolysis (20 L; aq. 2N NaOH) at RT for 3 hrs. The alkaline solution was then stirred with toluene (15 L) and the organic layer was separated on removal of solvent gave additional quantity of (S)-methylbenzylamine.

The aqueous solution was acidified with IM H2SO4 to pH 5-0 and then extracted with CH2CI2 (15 L). The organic layer was separated and the solvent was removed to give viscous mass which was stirred with n-hexane (10 L) for 30 minutes to give brownish solid (3.2 kg) which contains 90% R-Isomer (15) along with 8-10% of S-Isomer (13).
Example 16: Preparation of Compound (16)

The unwanted R-Isomer (15; 2.2 kg) and DCM (17.6 L) were taken into a reactor and to this DMF (66.0 L) and Pyridine (1.73 kg) were added. While stirring POCI3 (1.1 L) was added over a period of 1 hr keeping the temperature of the mixture below 40°C. The contents were stored for 12 hrs at room temperature (>95% conversion) the contents were transferred into 10% sodium bicarbonate solution (3 kg in 30 L of water) keeping the temperature between 0-10°C. The DCM layer was separated, washed with water (30 L) and the solvent was removed below 45°C to give 4.4 kg of the chloro compound (16).
Example 17: Preparation of deoxy compound (17)

Compound (16; 0.6 kg), methanol (40 L) and sodium bicarbonate (0.3 kg) were charged in a hydrogenator and to this 10% Pd/C (0.03 kg) in methanol (20 L) were added and hydrogenated at 40 psi for 5 hrs. The catalyst was removed by filtration and the solvent was removed. The compound was crystallized from 50% ethylacetate in hexane (10 L). The brownish product with purity of 95% was collected (0.45 kg)
Example 18: Preparation of compound (11) from deoxy compound (17)

Deoxy Compound (17; 1.9 kg) was dissolved in MeOH (24 L) and to this anhydrous potassium carbonate (0.7 kg) was added and oxygen was bubbled through the mixture for 2 hrs. The solution was cooled to below 10°C and slowly acidified with INH2SO4 (7.5 L) to pH 6. Removed methanol under reduced pressure, keeping the temperature below 50°C cooled to 20°C and diluted with water (5 L) and adjusted pH to 3. The aqueous solution was extracted twice with CH2CI2 (20 & 6 L). The solvent layer was washed with water (6 L) and evaporated to obtain compound (11).

We claim;

1. An efficient process for the preparation of (S)-Trione (14) comprising the following steps:

(a) condensing acetone with diethyl oxalate in presence of sodium methoxide in methanol to give mixture of compounds la and lb;

(b) reacting mixture of la and lb with ethyl orthoformate in ethanol using dodecylbenzene sulphonic acid as acid catalyst to obtain enol ether 2a and 2b;

(c) converting enol ether 2a and 2b to 2-pyridone derivative (3) by reacting with 2-cyanoacetamide in ketonic solvent in presence of potassium carbonate and further converting compound (3) to compound (4b) by reacting with methyl acrylate in presence of a radical inhibitor and potassium carbonate as base in DMSO followed by acidification;

(d) decarboxylating compound (4b) in acid mixture of acetic acid and conc. HCl in 1:1 ratio to obtain compound (5) followed by ketalization of compound (5) to obtain compound (6) with ethylene glycol in presence of trierthylsilyl chloride in presence of organic solvent;



(e) carbonylating compound (6) to obtain compound (7) with diethyl carbonate in presence of a mixture of sodium hydride and potassium tert- butoxide (3:leq) in an organic solvent;

(f) alkylating compound (7) to obtain compound (8) with ethyl bromide in presence of a phase transfer catalyst in THF at room temperature;

(g) hydrogenating compound (8) to acetamido derivative (9) with Raney nickel in acetic acid and acetic anhydride, which is reacted with sodium nitrite at low temperature to give intermediate (10) followed by bubbling oxygen through the solution of compound (10) to yield compound (11);

(h) resolving the racemic compound (11) with (S)-α-methylbenzyl amine at 80-100°C to yield desired (S,S)-amide (12a) followed by lactonisation of (12a) in presence of acetic acid to obtain compound (13) and deketalization with organic or mineral acid at room temperature in a polar medium to yield S-trione (14).

2. The process according to claim 1, wherein the ketonic solvent used in step (c) is selected from acetone or methyl ethyl ketone.

3. The process according to claim 1, wherein the radical inhibitor used in step (c) in the conversion of compound (3) to compound (4) is selected from 2,6-bis. tert. butyl-4-methylphenol.

4. The process according to claim 1, wherein the organic solvent used in step (d) in the conversion of compound (5) to compound (6) is selected from methylene dichloride, ethylene dichloride, chloroform and acetonitrile.

5. The process according to claim 1, wherein the solvent employed in step (e) is selected from methylene dichloride, 1,2 dimethoxy ethane.

6. The process according to claim 1, wherein the phase transfer catalyst used in the alkylating step (f) is selected from tetraalkyl ammonium iodide or TBAB.

7. The process according to claim 1, wherein the organic or mineral acid for deketalisation of compound (13) is selected from formic acid, trifluoroacetic acid, sulphuric acid.

8. The process according to claim 1, wherein the methyl acrylate used in step (c) is in the range of 2 to 4 equivalence.

9. The process according to claim 1, wherein the radical inhibitor used in step (c) is in the range of 0.1 -0.3mole.

10. The process according to claim 1, wherein the ethyl bromide used in step (f) is in the range of 1.5-2.5 equivalence.

11. The process according to claim 1, wherein the conversion of enol ether (2) to compound (4) is optionally carried out in one -pot.

12. A process for recyclization of (R,S) isomer (12b) to S-trione comprising the following steps;

(a) hydrolyzing isomer R,S amide (12b) at reflux to obtain compound (15),

(b) chlorinating the compound (15) in presence of a base to obtain compound (16),

(c) hydrogenolysis of compound (16) to obtain deoxy compound (17),

(d) converting compound (17) to the racemic compound (11) which is recycled to yield desired S-trione (14).

13. The process according to claim 11, wherein the chlorinating agent is selected from POCI3, PCI3 and SOCI2.

14. The process according to claim 11, wherein the base for step (b) is selected from pyridine, triethylamine or N, N-dimethyl-aminopyridine.

15. The process according to claim 11, wherein the hydrogenolysis of step (c) is carried out in presence of 5%Pd/C.

16. The process claimed in claim 1, wherein S-trione is 99.8% optically pure.